c.564G>T (W117C)
Eleven RCCs and 16 renal cysts from eight patients with VHL were analyzed. All patients had known germline VHL mutations. One male patient had a missense germline mutation (c.351G>T; p.W117C) in VHL gene and presented with bilateral RCC and cysts, CNS and retinal hemangioblastoma, and pancreatic cysts. Family history was not described for the patient.
A study investigated paraganglioma/pheochromocytoma tumors in a retrospective cohort and a prospective cohort. Some of these tumors were found with germline VHL mutations. Tumour ID 47 was bilateral PCC and a germline c.467A>C mutation in the VHL gene. Other phenotypic and demographic information was not available.
A study investigated paraganglioma/pheochromocytoma tumors in a retrospective cohort and a prospective cohort. Some of these tumors were found with germline VHL mutations. Tumour ID 40 and ID 41 (both from a 15 years old patient presenting with multiple benign tumors), and ID 42 (from a 40 years old patient presenting with multiple benign tumors) were PCC and found with a germline mutation in the VHL gene p.Leu178Pro. It is not clear if tumour samples 40 and 41 were taken from the same patient at 2 different time points or different patients. Other phenotypic and demographic information was not available.
In a study of 114 unrelated VHL affected families, germline mutations in the VHL gene were identified in 85 of the families. VHL mutations were detected in affected family members, but not in unaffected family members or 96 normal individuals, however it seems unaffected family members were not tested genetically for the mutations. Mutations in the VHL gene were detected by SSCP and DNA sequencing. Haplotypes were determined with four microsatellite polymorphic probes. The missense mutation L184P (c.551T>C) (In the paper noted as nucleotide position 764 and codon position 255 due to old reference transcript), was found in 2 individuals in family 3708. Both individuals were identified with renal cell carcinoma and one also presented with a CNS hemangioblastoma. Additional information regarding the family information, including a pedigree, were not provided. ACMG evidence codes: 'flag for PP4' since the patients phenotype and family history is consistent with VHL, 'flag for PP1' because there is co-segregation of variant with the phenotype in two members of the family.
GroupID: 3710
DiseaseAssertion: assumed VHL
GroupSize: 6
GroupNumberMales: N/A
GroupNumberFemales: N/A
GroupEthnicity: N/A
GroupAgeRange: N/A
GroupInfo: Familial VHL stated; 6 family members recorded with this mutation.
GroupPresentingHPOs: HP:0010797; HP:0009711; HP:0005584 (hemangioblastoma, retinal capillary hemangioma, renal cell carcinoma)
GroupHPOFreeText: all 6 members had CNS hemangioblastomas, 4/6 members had retinal angiomas (hemangiomas), and 3/6 had RCC
GroupNotHPOs: HP:0002666 (pheochromocytoma)
GroupNotHPOFreeText: N/A
GroupPreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: N/A
Variant: p.L135* (c.404T>A)
CaseProblemVariantFreeText: N/A
LegacyVariant: p.L206* (c.617T>A)
ClinVarID: N/A
CAID: CA351754021 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.404T%3EA
gnomAD: N/A
VariantEvidence: N/A
MutationType: stop_gained
CivicName: L135* (c.404T>A)
MultipleGeneVariants: N/A
GroupID: 3708
DiseaseAssertion: assumed VHL
GroupSize: 2
GroupNumberMales: N/A
GroupNumberFemales: N/A
GroupEthnicity: N/A
GroupAgeRange: N/A
GroupInfo: Familial VHL stated; 2 family members recorded with this mutation.
GroupPresentingHPOs: HP:0010797; HP:0005584 (hemangioblastoma, renal cell carcinoma)
GroupHPOFreeText: both (2) members has RCC and 1 member had hemangioblastoma
GroupNotHPOs: HP:0009711; HP:0002666 (retinal capillary hemangioma, pheochromocytoma)
GroupNotHPOFreeText: N/A
GroupPreviousTesting: N/A
PreviouslyPublished: 8956040
SupplementalData: N/A
Variant: p.L184P (c.551T>C)
CaseProblemVariantFreeText: N/A
LegacyVariant: p.L255P (c.764T>C)
ClinVarID: 419447 https://www.ncbi.nlm.nih.gov/clinvar/variation/419447/
CAID: N/A
gnomAD: N/A
VariantEvidence: N/A
MutationType: missense_variant; transition
CivicName: L184P (c.551T>C)
MultipleGeneVariants: N/A
PatientID: 9760
KindredID: 415
Case: Sex Unknown, Age Unknown, French
DiseaseAssertion: VHL
FamilyInfo: N/A
CohortInfo: Families were recruited from the French VHL Registry. Enrolment in the study required identification of the germline VHL mutation (currently 85% of the families included in the French VHL Registry) and available data regarding renal phenotype. A total of 126 families fulfilled these criteria.
CasePresentingHPOs: HP:0005584 (Renal cell carcinoma)
CaseHPOFreeText: Mild renal disease (simple renal cyst, multicystic kidney[s], small lesion [less than 10 mm in size] of unknown significance, or small solid tumor without indication for surgical removal [less than 30 mm in size]).
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: Phenotype and genotype information can be found in Supplementary Table S1.
Variant: Rearrangement
LegacyVariant: N/A
CaseProblemVariantFreeText: N/A
ClinVarID: N/A
CAID: N/A
gnomAD: N/A
VariantEvidence: N/A
MutationType: rearrangement_region
CivicName: Rearrangement
MultipleGeneVariants: N/A
Molecular and clinical analysis of 126 French VHL families tested for renal involvement revealed 92 different mutations. 90 of these families had renal involvement. The p.S80N (c.239G>A) germline variant of the VHL gene was detected in a family (ID 19). Members 697, 752 and 2682 presented with moderate renal disease (RCC). Members 759, 4070, 2596, 6632, 2367, 3255 and 3267 presented with unknown renal involvement. Member 4101 presented with severe renal disease (RCC). Members 2727 and 2728 had no renal involvement. The paper states that this family is previously reported in PMID 12202531 and/or 9829912.
GroupID: 23
DiseaseAssertion: VHL
GroupSize:3
GroupNumberMales: N/A
GroupNumberFemales: N/A
GroupEthnicity: French
GroupAgeRange: N/A
GroupInfo: 3 members of this family presented with the c.499C>T germline variant of the VHL gene. Member 1037 had no renal involvement. Members 1035 and 1036 had moderate renal disease (RCC). Families were recruited from the French VHL Registry. Enrolment in the study required identification of the germline VHL mutation (currently 85% of the families included in the French VHL Registry) and available data regarding renal phenotype. A total of 126 families fulfilled these criteria.
GroupPresentingHPOs: HP:0005584 (Renal cell carcinoma)
GroupHPOFreeText: Moderate renal disease (less than five solid lesions requiring surgical treatment, either unilateral or bilateral).
GroupNotHPOs: N/A
GroupNotHPOFreeText: N/A
GroupPreviousTesting: N/A
PreviouslyPublished: Paper states that this family is previously reported in PMID 12202531 and/or 9829912, where 15 individuals and 3 families respectively with this mutation are reported. It is unclear if one or both of these previously reported groups are the same as the current family. These previously reported individuals/families could alternatively correspond to family 1 or 50.
SupplementalData: Phenotype and genotype information can be found in Supplementary Table S1.
Variant: p.R167W (c.499C>T)
LegacyVariant: N/A
CaseProblemVariantFreeText: N/A
ClinVarID: 2218, https://www.ncbi.nlm.nih.gov/clinvar/variation/2218/
CAID: N/A
gnomAD: 0.000007954, https://gnomad.broadinstitute.org/variant/3-10191506-C-T?dataset=gnomad_r2_1
VariantEvidence: N/A
MutationType: missense_variant;transition
CivicName: R167W (c.499C>T)
MultipleGeneVariants: N/A
GroupID: 362
DiseaseAssertion: VHL
GroupSize: 2
GroupNumberMales: N/A
GroupNumberFemales: N/A
GroupEthnicity: French
GroupAgeRange: N/A
GroupInfo: 2 members of this family were found to harbor the c.395A>C germline variant of the VHL gene. Member 8813 had unknown renal involvement. Member 5862 presented with mild renal disease. Families were recruited from the French VHL Registry. Enrolment in the study required identification of the germline VHL mutation (currently 85% of the families included in the French VHL Registry) and available data regarding renal phenotype. A total of 126 families fulfilled these criteria.
GroupPresentingHPOs: HP:0009726 (Renal neoplasm)
GroupHPOFreeText: Mild renal disease (simple renal cyst, multicystic kidney[s], small lesion [less than 10 mm in size] of unknown significance, or small solid tumor without indication for surgical removal [less than 30 mm in size]).
GroupNotHPOs: N/A
GroupNotHPOFreeText: N/A
GroupPreviousTesting: N/A
PreviouslyPublished: Paper states that this family is previously reported in PMID 12202531, where 1 individual with this mutation is reported. It is unclear which of the members of this family this previously reported patient corresponds to.
SupplementalData: Phenotype and genotype information can be found in Supplementary Table S1.
Variant: p.Q132P (c.395A>C)
LegacyVariant: N/A
CaseProblemVariantFreeText: N/A
ClinVarID: 496063, https://www.ncbi.nlm.nih.gov/clinvar/variation/496063/
CAID: N/A
gnomAD: N/A
VariantEvidence: N/A
MutationType: missense_variant;transversion
CivicName: Q132P (c.395A>C)
MultipleGeneVariants: N/A
Germline mutations were identified in 300/469 (63%) of the families tested; 137 distinct intragenic germline mutations were detected.
Germline mutational data on VHL was gathered from various countries to assess variation in germline mutations that produce disease within different populations. Families were grouped according to three possible outcomes of disease: renal cell carcinoma without pheochromocytoma, renal cell carcinoma with pheochromocytoma, or pheochromocytoma alone. SSCP and denaturing gradient gel electrophoresis identified mutations in 300/469 (63%) of families affected with VHL. This germline familial VHL mutation (S80N (c.239G>A)) was taken from the Munich, university of Freiburg and Institute of Pathology database, with an unknown number of members belonging to Family ID 39CE. It was reported in the paper as c.452G>A due to a difference in transcript reference. As reported in Table 3, this mutation is found in VHL families without pheochromocytoma, and with renal cell carcinoma.
Germline mutations were identified in 300/469 (63%) of the families tested; 137 distinct intragenic germline mutations were detected.
GroupID/ KindredID: 85CA
DiseaseAssertion: VHL
GroupSize: N/A
GroupNumberMales: N/A
GroupNumberFemales: N/A
GroupEthnicity: N/A
GroupAgeRange: N/A
GroupInfo: This germline familial VHL mutation was taken from the Cambridge, Department of Pathology database, with an unknown number of members belonging to Family ID 85CA. Table 3 lists all ID and mutations associated with individuals possessing renal carcinoma, without pheochromocytoma.
GroupPresentingHPOs: HP:0005548 (renal cell carcinoma)
GroupHPOFreeText: Described as a VHL family with RCC, without pheochromocytoma. Other phenotypes are likely, however not detailed in this publication
GroupNotHPOs: HP:0002666 (pheochromocytoma)
GroupNotHPOFreeText: N/A
GroupPreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: N/A
Variant: p.C77Lfs*55 (c.228_229insC)
LegacyVariant: FS (c.441insC)
CaseProblemVariantFreeText: NM_000551.3:c.228_229insC automaps to c.228dupC
ClinVarID: N/A
CAID: CA658795177 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.228dupC
gnomAD: N/A
VariantEvidence: This paper declares this variant is predicted to compromise the Elongin-binding site by truncating the protein.
MutationType: plus_1_frameshift_variant; duplication
CivicName: C77fs (c.228dupC)
MultipleGeneVariants: N/A
Germline mutations were identified in 300/469 (63%) of the families tested; 137 distinct intragenic germline mutations were detected.
GroupID/ KindredID: 102CA
DiseaseAssertion: VHL
GroupSize: N/A
GroupNumberMales: N/A
GroupNumberFemales: N/A
GroupEthnicity: N/A
GroupAgeRange: N/A
GroupInfo: This germline familial VHL mutation was taken from the Cambridge, Department of Pathology database, with an unknown number of members belonging to Family ID 102CA. Table 3 lists all ID and mutations associated with individuals possessing renal carcinoma, without pheochromocytoma.
GroupPresentingHPOs: HP:0005548 (renal cell carcinoma)
GroupHPOFreeText: Described as a VHL family with RCC, without pheochromocytoma. Other phenotypes are likely, however not detailed in this publication
GroupNotHPOs: HP:0002666 (pheochromocytoma)
GroupNotHPOFreeText: N/A
GroupPreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: N/A
Variant: p.D126Rfs*6 (c.375_376insC)
LegacyVariant: FS (c.588insC)
CaseProblemVariantFreeText: c.375_376insC automaps to NM_000551.3:c.375dupC
ClinVarID: N/A
CAID: CA16621931 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.375dupC
gnomAD: N/A
VariantEvidence: This paper declares this variant is predicted to compromise the Elongin-binding site either by truncating the protein.
MutationType: duplication; plus_1_frameshift_variant
CivicName: D126fs (c.375dupC)
MultipleGeneVariants: N/A
Germline mutations were identified in 300/469 (63%) of the families tested; 137 distinct intragenic germline mutations were detected.
Germline mutational data on VHL was gathered from various countries to assess variation in germline mutations that produce disease within different populations. Families were grouped according to three possible outcomes of disease: renal cell carcinoma without pheochromocytoma, renal cell carcinoma with pheochromocytoma, or pheochromocytoma alone. SSCP and denaturing gradient gel electrophoresis identified mutations in 300/469 (63%) of families affected with VHL. This germline familial VHL mutation (G104Hfs*27 (c.309_310delTG)) was taken from the Cambridge, Department of Pathology database, with an unknown number of members belonging to Family ID 53CA. It was reported in the paper as c.522delTG due to a difference in transcript reference. As reported in Table 3, this mutation is found in VHL families without pheochromocytoma, and with renal cell carcinoma.
Germline mutations were identified in 300/469 (63%) of the families tested; 137 distinct intragenic germline mutations were detected.
Germline mutational data on VHL was gathered from various countries to assess variation in germline mutations that produce disease within different populations. Families were grouped according to three possible outcomes of disease: renal cell carcinoma without pheochromocytoma, renal cell carcinoma with pheochromocytoma, or pheochromocytoma alone. SSCP and denaturing gradient gel electrophoresis identified mutations in 300/469 (63%) of families affected with VHL. This germline familial VHL mutation (L158V (c.472C>G)) was taken from the Cambridge, Department of Pathology database, with an unknown number of members belonging to Family ID 91CA. It was reported in the paper as c.685C>G due to a difference in transcript reference. As reported in Table 3, this mutation is found in VHL families without pheochromocytoma, and with renal cell carcinoma.
Germline mutations were identified in 300/469 (63%) of the families tested; 137 distinct intragenic germline mutations were detected.
GroupID/ KindredID: 3708NCI
DiseaseAssertion: VHL
GroupSize: N/A
GroupNumberMales: N/A
GroupNumberFemales: N/A
GroupEthnicity: N/A
GroupAgeRange: N/A
GroupInfo: This germline familial VHL mutation was taken from the National Cancer Institute database, with an unknown number of members belonging to Family ID 3708NCI. Table 3 lists all ID and mutations associated with individuals possessing renal carcinoma, without pheochromocytoma.
GroupPresentingHPOs: HP:0005548 (renal cell carcinoma)
GroupHPOFreeText: Described as a VHL family with RCC, without pheochromocytoma. Other phenotypes are likely, however not detailed in this publication
GroupNotHPOs: HP:0002666 (pheochromocytoma)
GroupNotHPOFreeText: N/A
GroupPreviousTesting: N/A
PreviouslyPublished: 7728151
SupplementalData: N/A
Variant: p.L184P (c.551T>C)
LegacyVariant: p.L184P (c.764T>C)
CaseProblemVariantFreeText: N/A
ClinVarID: 419447 https://www.ncbi.nlm.nih.gov/clinvar/variation/419447/
CAID: N/A
gnomAD: N/A
VariantEvidence: This paper declares this variant is predicted to compromise the Elongin-binding site by location between codons 157 and 189.
MutationType: missense_variant; transition
CivicName: L184P (c.551T>C)
MultipleGeneVariants: N/A
Germline mutations were identified in 300/469 (63%) of the families tested; 137 distinct intragenic germline mutations were detected.
Germline mutational data on VHL was gathered from various countries to assess variation in germline mutations that produce disease within different populations. Families were grouped according to three possible outcomes of disease: renal cell carcinoma without pheochromocytoma, renal cell carcinoma with pheochromocytoma, or pheochromocytoma alone. SSCP and denaturing gradient gel electrophoresis identified mutations in 300/469 (63%) of families affected with VHL. This germline familial VHL mutation (V170F (c.508G>T)) was taken from the Cambridge, Department of Pathology database, with an unknown number of members belonging to Family ID 26CA. It was reported in the paper as c.721G>T due to a difference in transcript reference. As reported in Table 4, this mutation is found in VHL families with pheochromocytoma. Other phenotypes are likely, including renal cell carcinoma, however not detailed here.
Germline mutations were identified in 300/469 (63%) of the families tested; 137 distinct intragenic germline mutations were detected.
GroupID/ KindredID: 12BMS
DiseaseAssertion: VHL
GroupSize: N/A
GroupNumberMales: N/A
GroupNumberFemales: N/A
GroupEthnicity: N/A
GroupAgeRange: N/A
GroupInfo: This germline familial VHL mutation was taken from the Bristol Myers Squibb database, with an unknown number of members belonging to family ID: Family 12BMS. Table 5 lists all ID and mutations associated with individuals without detailed clinical information.
GroupPresentingHPOs: N/A
GroupHPOFreeText: Described as multiple VHL families without detailed clinical information. Other phenotypes are possible, however not detailed here.
GroupNotHPOs: N/A
GroupNotHPOFreeText: N/A
GroupPreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: N/A
Variant: p.S65* (c.194C>A)
LegacyVariant: p.S65* (c.407C>A)
CaseProblemVariantFreeText: N/A
ClinVarID: 223161 https://www.ncbi.nlm.nih.gov/clinvar/variation/223161/
CAID: N/A
gnomAD: N/A
VariantEvidence: This paper declares this variant is predicted to compromise the Elongin-binding site by truncating the protein.
MutationType: stop_gained
CivicName: S65* (c.194C>A)
MultipleGeneVariants: N/A
Germline mutations were identified in 300/469 (63%) of the families tested; 137 distinct intragenic germline mutations were detected.
Germline mutational data on VHL was gathered from various countries to assess variation in germline mutations that produce disease within different populations. Families were grouped according to three possible outcomes of disease: renal cell carcinoma without pheochromocytoma, renal cell carcinoma with pheochromocytoma, or pheochromocytoma alone. SSCP and denaturing gradient gel electrophoresis identified mutations in 300/469 (63%) of families affected with VHL. This germline familial VHL mutation (W88S (c.263G>C)) was taken from the Department of Uroglogy, Yokohama database, with an unknown number of members belonging to Family ID 8YO. It was reported in the paper as c.476G>C due to a difference in transcript reference. As reported in Table 3, this mutation is found in VHL families without pheochromocytoma, and with renal cell carcinoma.
Chromosomal analysis confirmed the presence of 384delT of frame-shift mutation in exon 2 of the tumor suppressor, E3 ubiquitin protein ligase, vHL gene.
ArticleReferenceSequence: Not specified – Assumption: variants assumed to have been documented by the author under reference sequence NM_000551.3
GenotypingMethod: Chromosomal analysis not specified further
SamplingMethod: N/A - Not stated
CASE REPORT [Image Omitted. Please see PDF] A 19-year-old Saudi male presented to the emergency department with one-week history of polyuria and polydipsia. Physical examination findings were unremarkable. His father had died as a complication of metastatic renal carcinoma. Initial workup demonstrated random blood glucose of 16.3 mmol/L and HbA1C of 9.1%. Urinalysis was positive for ketone bodies, and blood analysis was positive for traces of ketone bodies. Patient was acidotic with pH of 7.3 and bicarbonate levels of 19 mmol/L. A presumptive diagnosis of diabetic ketoacidosis (DKA) was made; immune markers including glutamic acid decarboxylase (GAD) autoantibodies and islet cell autoantibodies were sent to exclude type I diabetes mellitus and maturity onset diabetes of the young. Intravenous insulin infusion and other appropriate management were initiated to control blood sugars and to correct the associated DKA. Later, the diagnosis of type I diabetes mellitus was confirmed with the presence of islet cell autoantibodies and that C-peptide level were within normal range. [Image Omitted. Please see PDF] Ultra-sound abdomen was performed as the patient complained of persistent abdominal pain even after correction of DKA. Ultrasound abdomen demonstrated an incidental finding of a well-defined hypo-echoic soft tissue mass measuring 3.7 x 4.7 cm in the left supra-renal region. Computerized tomography (CT) scan was performed for further evaluation. It demonstrated a 3.7 x 4.0 cm rounded lesion in the left adrenal gland with intense enhancement, suggestive of pheochromocytoma. A small hypo-dense lesion was also noted in the left renal upper pole, measuring 2.3 cm, with heterogeneous enhancement suggestive of a solid mass. The CT scan also demonstrated multiple rounded cystic lesions in the head, body, neck and tail of the pancreas representing pancreatic cysts. The above findings collectively were suggestive of phakomatosis disorders, in particular, vHL disease. Chromosomal studies were sent for detection of genetic mutations and confirmation of the diagnosis. MRI abdomen was highly suggestive of a left sided pheochromocytoma (Figure 1). It also demonstrated multiple cystic lesions in the pancreas (Figure 2) and bilateral cortical lesions in the kidneys, which demonstrated internal septal enhancement in the post gadolinium injection phase, highly indicative of renal cell carcinoma. Nuclear medicine scan demonstrated increased tracer uptake in the left suprarenal gland. Meanwhile, laboratory studies demonstrated increased serum normetanephrine level of 11.80 nmol/l, urine metanephrine level of 400nmol/24hrs, and urine normetanephrine level of 1210 nmol/24hrs. Serum cortisol, aldosterone and renin levels were within normal limits. A diagnosis of pheochromocytoma was confirmed and patient was started on anti-hypertensive medications and scheduled for surgical removal of the pheochromocytoma and the suspicious renal masses. Patient underwent robot assisted laparoscopic left adrenalectomy and left renal mass excision. Two renal nodules were removed. The post-operative course was unremarkable and patient was discharged home in stable condition. Histopathologic evaluation confirmed the diagnosis of pheochromocytoma; the renal masses were determined as renal clear cell carcinoma Furham grade I
PatientID: 1 (case)
KindredID: 1
Case: M,19Y0M, South Asian (Saudi)
DiseaseAssertion: assumed VHL
FamilyInfo: History of family showed that his father had died as a complication of metastatic renal carcinoma. Screening was done for the family. 3 of his 8 siblings tested positive for the 384delT mutation, although no phenotypes for them was given.
CasePresentingHPOs: HP:0100651; HP:0006748; HP:0001737; HP:0005584 (Type I diabetes mellitus; adrenal pheochromocytoma; pancreatic cysts; renal cell carcinoma)
CaseHPOFreeText: The young man presented with primary symptoms of polyuria and polydipsia, and was later found to be in diabetic ketoacidosis (diagnosed with diabetes mellitus type I). He had persistent abdominal pain (later showing left sided pheochromocytoma (3.7 x 4.0 cm rounded lesion in the left adrenal gland) and right sided renal cell carcinoma (measuring 2.3 cm, with heterogeneous enhancement suggestive of a solid mass)). The CT scan also demonstrated multiple rounded cystic lesions in the head, body, neck and tail of the pancreas representing pancreatic cysts. Bilateral cortical lesions in the kidneys also demonstrated internal septal enhancement in the post gadolinium injection phase, highly indicative of renal cell carcinoma.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: N/A
Variant: p.L129Trpfs*30 (c.384delT)
LegacyVariant: N/A
CaseProblemVariantFreeText: N/A
ClinVarID: N/A
CAID: CA70049452 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.384delT
gnomAD: N/A
VariantEvidence: N/A
MutationType: minus_1_frameshift_variant
CivicName: N/A
MultipleGeneVariants: N/A
VHL-Related Neuroendocrine Neoplasms And Beyond: An Israeli Specialized Center Real-Life Report
PMID: 33471715
Gene: VHL
StandardizedReferenceSequence: NM_000551.3
GroupID: 33
DiseaseAssertion: assumed VHL
GroupSize: 3
GroupNumberMales: N/A
GroupNumberFemales: N/A
GroupEthnicity: N/A
GroupAgeRange: N/A
GroupInfo: 3 of the 573 patients discussed in this paper were found to have the following mutation belonging to 2 families altogether.
GroupPresentingHPOs: HP:0006880; HP:0005584; HP:0009711 (cerebellar hemangioblastoma; renal cell carcinoma; retinal capillary hemangioma)
GroupHPOFreeText: 1 patient had retinal angiomas diagnosed at age 18Y, 3 had cerebellar hemangioblastomas diagnosed at mean age of 18Y, and 1 had RCC diagnosed at 50Y
GroupNotHPOs: HP:0002666 (pheochromocytoma)
GroupNotHPOFreeText: N/A
GroupPreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: Supplementary Table S1.
Variant: p.R176Gfs*26 (c.526delA)
LegacyVariant: N/A
CaseProblemVariantFreeText: N/A
ClinVarID: 625257 https://www.ncbi.nlm.nih.gov/clinvar/variation/625257/
CAID: N/A
gnomAD: N/A
VariantEvidence: N/A
MutationType: minus_1_frameshift_variant
CivicName: R176fs (c.526del)
MultipleGeneVariants: N/A
GroupID: 70
DiseaseAssertion: assumed VHL
GroupSize: 2
GroupNumberMales: N/A
GroupNumberFemales: N/A
GroupEthnicity: N/A
GroupAgeRange: N/A
GroupInfo: 2 of the 573 patients discussed in this paper were found to have identical variants. This mutation (c.395A>C) was found in 1 VHL family with 2 patients.
GroupPresentingHPOs: HP:0009711; HP:0006880; HP:0005584 (retinal capillary hemangioma; cerebellar hemangioblastoma; renal cell carcinoma)
GroupHPOFreeText: 1/2 patient had cerebellar hemangioblastoma (CHB) at 18Y, 1/2 had retinal capillary hemangioma (RH) at 37Y, and 1/2 had RCC at 49Y. Unclear as to which of the two patients these HPOs are paired to.
GroupNotHPOs: HP:0002666 (pheochromocytoma)
GroupNotHPOFreeText: N/A
GroupPreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: Supplementary Table S1.
Variant: p.Q132P (c.395A>C)
CaseProblemVariantFreeText: N/A
LegacyVariant: N/A
ClinVarID: 496063 https://www.ncbi.nlm.nih.gov/clinvar/variation/496063/
CAID: N/A
gnomAD: N/A
VariantEvidence: N/A
MutationType: missense_variant;transversion
CivicName: Q132P (c.395A>C)
MultipleGeneVariants: N/A
ArticleReferenceSequence: NM_000551.2
GenotypingMethod: VHL mutation analysis of the pVHL18 coding sequence and flanking intronic sequences was performed by direct sequencing. Southern and/or multiplex ligation-dependent probe amplification (MLPA) analysis.
SamplingMethod: whole blood
GroupID: 8
Case: 37Y0M, Sex Unknown, Ethnicity Unknown
DiseaseAssertion: assumed VHL
FamilyInfo: 1 of the 573 patients discussed in this paper were found to have this variant. This mutation was found in 1 VHL family with a single patient.
CasePresentingHPOs: HP:0005584; HP:0009711; HP:0006880 (renal cell carcinoma; retinal capillary hemangioma; cerebellar hemangioblastoma)
CaseHPOFreeText: patient had retinal angiomas diagnosed at 28Y, cerebellar hemangioblastomas diagnosed at 22Y, and renal cell carcinoma diagnosed at 37Y.
CaseNotHPOs: HP:0002666 (pheochromocytoma)
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: Supplementary Table S1.
Variant: p.R177* (c.529A>T)
CaseProblemVariantFreeText: N/A
LegacyVariant: N/A
ClinVarID: 625258 https://www.ncbi.nlm.nih.gov/clinvar/variation/625258/
CAID: N/A
gnomAD: N/A
VariantEvidence: N/A
MutationType: stop_gained
CivicName: R177* (c.529A>T)
MultipleGeneVariants: N/A
VHL DNA sequence analysis depicting part of exon 3 sequence of the VHL gene with the 491A>G mutation (arrow) in the 2.75-year-old girl (A) and her father (B). [Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com.]
A 2.75 year old patient (32 month-old girl) presented with a pheochromocytoma. Genetic sequencing (not specified) revealed a c.491A>G (p.Gln164Arg) heterozygous germline mutation in exon 3 of the VHL gene. Sequencing of her mother, father, a sibling, and her paternal grandparents revealed that the mutation was present only in her father, and was de-novo in her father. Upon screening, her father (a 31 year old male) presented with a retinal angioma, an adenoma of right adrenal gland, a right-sided renal cyst, an epidydymal cyst, a contrast-enhancing lesion in the pancreas, and bilateral pheochromocytomas.
2 France c.583C>T p.Gln195*
Patients with ELSTs were identified and included in the International Endolymphatic Sac Tumor Registry. The registry contained 93 patients as of July 2014, and of those, 25 were sporadic, and 68 associated with VHL. Patients with ELSTs and clinically confirmed diagnoses of VHL were included in this study. Statistics of this VHL subgroup are as follows: mean age 30, 62% female, 91% symptomatic, 54% with retinal angioma, 72% with CNS hemangioblastoma, 46% with renal cell carcinoma, 19% with pheochromocytoma, and 12% with pancreatic neuroendocrine tumour. In the data from this study, only endolymphatic sac tumours can be confirmed as a phenotype for this mutation (c.583C>T), which was found in 2 individuals from France.
2 complete deletions
27 index patients suspected of having VHL disease from unrelated Chinese families and their relatives were studied. The nucleotide were numbered according to the sequence numbering by Latif et al, 1993 and this was converted to NM_000551.3. The paper did not differentiate between a pancreatic cysts and tumor and presented these together as a 'pancreatic lesion'. The paper summarized the phenotypes of the families together. Family 21 and 25 were each one member (proband) each and were found with complete VHL deletions. Proband 21 had only hemangioblastoma and genetic testing of her parents confirmed a de novo mutation. Proband 25 was found with hemangioblastoma, retinal angioma and pancreatic lesion. Proband 25 had no family history of VHL but parents were not available for genetic testing so de novo mutation cannot be assessed. ACMG PVS1
12 missenses
GroupID/ KindredID: 19
DiseaseAssertion: assumed VHL
GroupSize: 3
GroupNumberMales: N/A
GroupNumberFemales: N/A
GroupEthnicity: Chinese
GroupAgeRange: N/A
GroupInfo: With a family history, 3 family members were recorded in this group with the given mutation.
GroupPresentingHPOs: HP:0010797; HP:0005584 (hemangioblastoma; renal cell carcinoma)
GroupHPOFreeText: all (3) members had CNS hemangioblastomas, and 1 had RCC
GroupNotHPOs: HP:0009711; HP:0002666; HP:0001732 (retinal capillary hemangioma; pheochromocytoma; pancreatic lesion)
GroupNotHPOFreeText: No family members appeared to have the above manifestations.
GroupPreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: N/A
Variant: p.C162W (c.486C>G)
CaseProblemVariantFreeText: N/A
LegacyVariant: p.C162W (c.699C>G)
ClinVarID: 223227 https://www.ncbi.nlm.nih.gov/clinvar/variation/223227/
CAID: N/A
gnomAD: N/A
VariantEvidence: N/A
MutationType: missense_variant; transversion
CivicName: C162W (c.486C>G)
MultipleGeneVariants: N/A
R238W
PatientID: None
KindredID: 386
Case: M, 15Y0M, Polish
DiseaseAssertion: Pheochromocytoma
FamilyInfo: One of the patient’s brothers carried the mutation and presented with bilateral pheochromocytoma at 11Y. The patient’s mother also carried the mutation and presented with bilateral pheochromocytoma at 41Y.
CasePresentingHPOs: HP:0002666 (Pheochromocytoma)
CaseHPOFreeText: The patient presented with unilateral pheochromocytoma at 15Y.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: RET
PreviouslyPublished: N/A
SupplementalData: N/A
Variant: p.R167W(c.499C>T)
LegacyVariant: p.R238W(c.712C>T)
ClinVarID: 2218, http://www.ncbi.nlm.nih.gov/clinvar/variation/2218
gnomAD: 3:10191506 C / T, http://gnomad.broadinstitute.org/variant/3-10191506-C-T
VariantEvidence: N/A
MutationType: missense_variant;transition
CivicName: R167W(c.499C>T)
MultipleGeneVariants: N/A
R238W
PatientID: None
KindredID: 386
Case: M, 11Y0M, Polish
DiseaseAssertion: Pheochromocytoma
FamilyInfo: One of the patient’s brothers carried the mutation and presented with unilateral pheochromocytoma at 15Y. The patient’s mother also carried the mutation and presented with bilateral pheochromocytoma at 41Y.
CasePresentingHPOs: HP:0002666 (Pheochromocytoma)
CaseHPOFreeText: The patient presented with bilateral pheochromocytoma at 11Y.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: RET
PreviouslyPublished: N/A
SupplementalData: N/A
Variant: p.R167W(c.499C>T)
LegacyVariant: p.R238W(c.712C>T)
ClinVarID: 2218, http://www.ncbi.nlm.nih.gov/clinvar/variation/2218
gnomAD: 3:10191506 C / T, http://gnomad.broadinstitute.org/variant/3-10191506-C-T
VariantEvidence: N/A
MutationType: missense_variant;transition
CivicName: R167W(c.499C>T)
MultipleGeneVariants: N/A
PMID: 12053037
PatientID: 1 (case)
KindredID: 1
Case: M, 9Y0M, Ethnicity Unknown
DiseaseAssertion: VHL
FamilyInfo: N/A - Details about the family history of this boy are unknown because the father left the family and his relations are unable to be found. Ten siblings from different fathers are healthy.
CasePresentingHPOs: HP:0002668; HP:0002666 (paraganglioma; pheochromocytoma)
CaseHPOFreeText: metachronous paraganglioma adjacent to the opposite adrenal gland. A retropleural tumor was confirmed by MRI (of the fourth thoracic vertebra). MRI of the abdomen revealed a binodular tumor of 5 ! 2 ! 3 cm cranially and medially to the right kidney
CaseNotHPOs: N/A
CaseNotHPOFreeText: Internal and skin examination were unremarkable, especially café-au-lait spots of the skin were not present.
CasePreviousTesting: RET
PreviouslyPublished: N/A
SupplementalData: N/A
Variant: p.S65A (c.193T>G)
LegacyVariant: (c.406T>G)
CaseProblemVariantFreeText: A point mutation (406 T>G) found on exon 1, leads to the assumption of reference sequence used and Latif et al. (1993), translating to NM_000551.3 (c.406T>G).
ClinVarID: 223160 https://www.ncbi.nlm.nih.gov/clinvar/variation/223160/
CAID: N/A
gnomAD: N/A
VariantEvidence: N/A
MutationType: missense_variant;transversion
CivicName: S65A (c.193T>G)
MultipleGeneVariants: N/A
PatientID: V240
KindredID: V240
Case: Sex Unknown, Age Unknown, French
DiseaseAssertion: VHL
FamilyInfo: N/A
CasePresentingHPOs: HP:0002666 (Pheochromocytoma)
CaseHPOFreeText: Diagnosed with VHL Type 2A.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: N/A
Variant: p.T157I (c.470C>T)
LegacyVariant: N/A
CaseProblemVariantFreeText: N/A
ClinVarID: 223223, https://www.ncbi.nlm.nih.gov/clinvar/variation/223223/
CAID: N/A
gnomAD: N/A
VariantEvidence: N/A
MutationType: missense_variant;transition
CivicName: T157I (c.470C>T)
MultipleGeneVariants: N/A
Screening of 92 unrelated patients with VHL disease revealed 61 DNA variants. No variants were found in 96 control cases. Direct sequencing on peripheral blood was systematically performed on exon 1 PCR products. Southern blotting was used to search for larger alterations to the gene. The L188P (c.563T>C) missense mutation was found in a VHL type 1 (no pheochromocytoma) patient (patient no. V269). Five unaffected family members were negative for the variant.
GroupID: V32
DiseaseAssertion: VHL
GroupSize:2
GroupNumberMales: N/A
GroupNumberFemales: N/A
GroupEthnicity: N/A
GroupAgeRange: N/A
GroupInfo: Two family members had the same VHL gene mutation.
FamilyInfo: Positive.
GroupPresentingHPOs: HP:0002666 (pheochromocytoma)
GroupHPOFreeText: N/A
GroupNotHPOs: N/A
GroupNotHPOFreeText: N/A
GroupPreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: N/A
Variant: p.R161Q(c.482G>A)
LegacyVariant: N/A
CaseProblemVariantFreeText: N/A
ClinVarID: 182983 https://www.ncbi.nlm.nih.gov/clinvar/variation/182983/
CAID: N/A
gnomAD: N/A
VariantEvidence: N/A
MutationType: missense_variant;transition
CivicName:R161Q(c.482G>A)
MultipleGeneVariants: N/A
PMID: 21528239
Two Swedish families with von Hippel-Lindau disease (VHL) were analyzed. Family B consists of 4 members across 2 generations. Patient I:1 (proband) is a female with renal cell carcinoma and cerebellar hemangioblastomas. Genetic analysis of blood samples revealed a frameshift mutation N174fs (c.520insAA, originally written in paper was legacy notation c.732insAA) with a downstream premature stop codon at position 201. Genetic analysis of her two children also confirmed the mutation: her son, patient II:1, had cerebellar hemangioblastoma and her daughter, patient II:2, was asymptomatic. The proband's partner (I:2) had no mutation and no VHL phenotype. ACMG: PP4
Nine patients were diagnosed with pheochromocytoma. Lumbal spinal hemangioblastoma and pancreatic neuroendocrine tumor without pheochromocytoma were detected in one patient. In patients with pheochromocytoma, additional tumors, such as retinal angioma, renal cell carcinoma, pancreatic serous cystadenoma, and pancreatic neuroendocrine tumors were detected. All patients were diagnosed as VHL syndrome type 2B.
PatientID: III-1
KindredID: 1
Case: M, 36Y0M, Turkish
DiseaseAssertion: VHL
FamilyInfo: 17 family members from three generations were examined with the c.445G>T mutation and diagnosed with VHL type 2B. 11 individuals had clinical manifestations and 6 were asymptomatic carriers. One additional member (II-9) had passed before testing however were likely a carrier of the mutation. This patient’s mother, brother, two daughters, and more, had the mutation. See Fig. 1 for full family pedigree.
CasePresentingHPOs: HP:0006748; HP:0005584; HP:0030405 (adrenal pheochromocytoma; renal cell carcinoma; pancreatic endocrine tumor)
CaseHPOFreeText: Right adrenal (nonfunctional) pheochromocytoma, had a history of bilateral adenomectomy due to bilateral pheochromocytoma diagnosed when he was 12. He also has bilateral RCC and pancreatic neuroendocrine tumors
CaseNotHPOs: HP:0030393; HP:0009715 (endolymphatic sac tumor, papillary cystadenoma of the epididymis)
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: N/A
Variant: p.A149S (c.445G>T)
LegacyVariant: N/A
CaseProblemVariantFreeText: N/A
ClinVarID: 127829 https://www.ncbi.nlm.nih.gov/clinvar/variation/127829/
CAID: N/A
gnomAD: N/A
VariantEvidence: N/A
MutationType: missense_variant;transversion
CivicName: A149S (c.445G>T)
MultipleGeneVariants: N/A
in seven of the asymptomatic family members.
PatientID: IV-2
KindredID: 1
Case: F, Age Unknown, Turkish
DiseaseAssertion: asymptomatic
FamilyInfo: 17 family members from three generations were examined with the c.445G>T mutation and diagnosed with VHL type 2B. 11 individuals had clinical manifestations and 6 were asymptomatic carriers. One additional member (II-9) had passed before testing however were likely a carrier of the mutation. This patient’s father, sister, grandmother and more, had the mutation. See Fig. 1 for full family pedigree.
CasePresentingHPOs: N/A
CaseHPOFreeText: None - described as a carrier of the p.A149S mutation, with no clinical manifestations. Their asymptomatic work up could have been due to the individual's young age
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: N/A
Variant: p.A149S (c.445G>T)
LegacyVariant: N/A
CaseProblemVariantFreeText: N/A
ClinVarID: 127829 https://www.ncbi.nlm.nih.gov/clinvar/variation/127829/
CAID: N/A
gnomAD: N/A
VariantEvidence: N/A
MutationType: missense_variant;transversion
CivicName: A149S (c.445G>T)
MultipleGeneVariants: N/A
Clinical presentation of Von Hippel Lindau syndrome type 2B associated with VHL p.A149S mutation in a large Turkish family
PMID: 23673869
Gene: VHL
StandardizedReferenceSequence: NM_000551.3
recognized in a large family that originated in Newfoundland but has some members who live in New Brunswick and Ontario. A collaborative investigation was begun in 1982 to document the number of affected members and the extent of their disease and to improve management of the disease. The condition has been documented in 38 members of the family, 28 living and 10 dead. The most common manifestations are retinal angioma (present in 60% of the gene carriers) and pheochromocytoma (present in 53%). Of the 28 living affected members 14 had been identified before the study began. Only 3 of the 14 patients in whom the disease was subsequently diagnosed presented with symptoms; in the remaining 11 the condition was detected by routine screening. Overall the mean age at the time of diagnosis was 23 years; in the 21 affected members of the fourth generation it was 18 years.
PatientID: III-4
KindredID: 1
Case: F, Age Unknown, Ethnicity Unknown
DiseaseAssertion: Assumed VHL
FamilyInfo: 38 family members had been affected at the date of 1986, and 10 had passed away. Pheochromocytoma, cerebellar, spinal and retinal hemangioblastomas, and various cysts were clinical manifestations of VHL seen throughout the family. This female (III-4) appears to have inherited this disease from her mother and has passed it onto to her daughter thereafter. See Fig. 1 for family pedigree.
CasePresentingHPOs: HP:0009711 (retinal capillary hemangioma)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: N/A
Variant: p.R167W (c.499C>T)
LegacyVariant: N/A
CaseProblemVariantFreeText: Although never given at the time of this publication, the germline mutation is confirmed in this family in later publications (PMID 7987306; 29437867) for this specific family. It is only here assumed this member had the VHL mutation.
ClinVarID: 2218, https://www.ncbi.nlm.nih.gov/clinvar/variation/2218/
CAID: N/A
gnomAD: 0.000007954, https://gnomad.broadinstitute.org/variant/3-10191506-C-T?dataset=gnomad_r2_1
VariantEvidence: N/A
MutationType: missense_variant;transition
CivicName: R167W (c.499C>T)
MultipleGeneVariants: N/A
recognized in a large family that originated in Newfoundland but has some members who live in New Brunswick and Ontario. A collaborative investigation was begun in 1982 to document the number of affected members and the extent of their disease and to improve management of the disease. The condition has been documented in 38 members of the family, 28 living and 10 dead. The most common manifestations are retinal angioma (present in 60% of the gene carriers) and pheochromocytoma (present in 53%). Of the 28 living affected members 14 had been identified before the study began. Only 3 of the 14 patients in whom the disease was subsequently diagnosed presented with symptoms; in the remaining 11 the condition was detected by routine screening. Overall the mean age at the time of diagnosis was 23 years; in the 21 affected members of the fourth generation it was 18 years.
PatientID: II-1
KindredID: 1
Case: F, Age Unknown (deceased), Ethnicity Unknown
DiseaseAssertion: Assumed VHL
FamilyInfo: 38 family members had been affected at the date of 1986, and 10 had passed away. Pheochromocytoma, cerebellar, spinal and retinal hemangioblastomas, and various cysts were clinical manifestations of VHL seen throughout the family. This woman (II-1) appears to have inherited this disease from her father, and passed it onto her 6 children, and many kin thereafter. See Fig. 1 for family pedigree.
CasePresentingHPOs: HP:0006880; HP:0009711 (cerebellar hemangioblastoma, retinal capillary hemangioma)
CaseHPOFreeText: Described as “probable” cerebellar hemangioblastoma and “probable” retinal angioma. No further details were provided.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: N/A
Variant: p.R167W (c.499C>T)
LegacyVariant: N/A
CaseProblemVariantFreeText: Although never given at the time of this publication, the germline mutation is confirmed in this family in later publications (PMID 7987306; 29437867) for this specific family. It is only assumed this member had the VHL mutation.
ClinVarID: 2218, https://www.ncbi.nlm.nih.gov/clinvar/variation/2218/
CAID: N/A
gnomAD: 0.000007954, https://gnomad.broadinstitute.org/variant/3-10191506-C-T?dataset=gnomad_r2_1
VariantEvidence: N/A
MutationType: missense_variant;transition
CivicName: R167W (c.499C>T)
MultipleGeneVariants: N/A
Gene symbol: VHL. Disease: pancreatic cancer
PMID: 10942118
Gene: VHL
StandardizedReferenceSequence: NM_000551.3
c.499C > T p.Arg167Trp
216 patients with clinically expected VHL disease due to family history or presence of VHL typical tumours were routinely examined in an eye centre in Germany between January 2019 and January 2020, majority of which were of European descent (~95%). Since data on the genotype–phenotype correlation of the onset of Retinal Hemangioblastoma (RH) is scarce in relation to VHL disease, this study wanted to inversitage the relationship between VHL gene variants (truncating vs single amino acid substitutions) and the ocular phenotype of the disease. 42 different rare VHL gene variants in 148 patients were detected - some of whom had RH and some who did not. Although date of onset of RH, as well as data on central nervous system haemangioblastomas (CNSH), pheochromocytoma/paraganglioma (PPGL), clear cell renalcell carcinoma (ccRCC) and pancreatic neuroendocrine neoplasm (PNEN) were collected, it was not reported on a per patient basis and therefore could not be discussed per variant. There was 1 patient reported with c.499C>T (p.R167W). This member presented with retinal hemangiomas. No family information was provided.
10 (67)
GroupID: 2a
DiseaseAssertion: VHL
GroupSize: 10
GroupNumberMales: N/A
GroupNumberFemales: N/A
GroupEthnicity: N/A
GroupAgeRange: N/A
GroupInfo: a retrospective cohort study from an eye centre in Germany involved 148 VHL patients and their genetic data involved in retinal capillary hemangiomas.
GroupPresentingHPOs: HP:0009711 (retinal capillary hemangioma)
GroupHPOFreeText: These 10/15 patients with a VHL gene deletion had retinal capillary hemangiomas. Other VHL manifestations were discussed but not per- variant.
GroupNotHPOs: N/A
GroupNotHPOFreeText: N/A
GroupPreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: Yes - Supplementary Table S1
Variant: VHL gene deletion
LegacyVariant: N/A
GroupProblemVariantFreeText: N/A
ClinVarID: N/A
CAID: N/A
gnomAD: N/A
VariantEvidence: N/A
MutationType: deletion
CivicName: Null (Complete Deletion)
MultipleGeneVariants: N/A
Serous Cystic Neoplasms of the Whole Pancreas in a Patient with von Hippel-Lindau Disease
PMID: 21673464
Gene: VHL
StandardizedReferenceSequence: NM_000551.3
21 missense mutations
Among patients prospectively followed by the members of the French VHL Study Group, 35 consecutive patients with well-documented endocrine pancreatic tumour (20 women and 15 men; median age,37 [21Y-57] years) were included. The data from 7 patients with EPT have been partially reported previously in Hammel et al., 1995;2000. All 35 patients had VHL germline mutations and were assessed for the presence of pheochromocytoma and renal cancer in addition to pancreatic tumours. The presence of other phenotypes was not described. The c.500G>A mutation was found in 2 unrelated patients. Patient no 13 from family 354 presented with pancreatic endocrine tumour and pheochromocytoma. Patient no. 29 from family 372 presented with pancreatic endocrine tumour and pheochromocytoma. No family history was mentioned. The patients' phenotypes are highly specific to VHL disease (PP4) and disease-causing missense variants are common in VHL disease (PP2). Further, the mutation is occuring at a VHL hotspot (PM1).
21 missense mutations
PatientID: 9
KindredID: 81
Case: Sex unknown, Age unknown, French
DiseaseAssertion: VHL
FamilyInfo: One other member belonging to family 81 was mentioned (Patient: 1). This patient was found to have a pancreatic endocrine tumour without pheochromocytoma or renal cell carcinoma.
CasePresentingHPOs: HP:0030405; HP:0002666 (pancreatic endocrine tumour, pheochromocytoma)
CaseHPOFreeText: N/A
CaseNotHPOs: HP:0005584 (renal cell carcinoma)
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: N/A
Variant: p.V170G (c.509T>G)
LegacyVariant: N/A
CaseProblemVariantFreeText: N/A
ClinVarID: N/A
CAID: CA351756196 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.509T%3EG
gnomAD: N/A
VariantEvidence:N/A
MutationType: missense_variant;transversion
CivicName: V170G (c.509T>G)
MultipleGeneVariants: N/A
Association of urinary bladder paragangliomas with germline mutations in the SDHB and VHL genes
PMID: 25683602
Gene: VHL
StandardizedReferenceSequence: NM_000551.3
PatientID: VI-6
KindredID: 2
Case: M, Age Unknown, German
DiseaseAssertion: VHL
FamilyInfo: Family 2 is comprised of 131 individuals over six generations including 65 members (50% of those at risk) with VHL type 2A (72% clinically affected, 12% obligate carriers, and 15% positive genetic analysis alone) and nearly equal gender distribution for affected status (54% male). An additional six members (II-3, II-4, II -5, III-1, III-2, and III-3) are suspected to have VHL without confirmation. Of note, the nuclear family (branch IV-13) contains 13 siblings, of whom 12 have been diagnosed with pheo. The presenting tumor types in Family 2 were pheo (70%), HB (17%), and RA (13%). No Family 2 member had RCC as the initial manifestation. Distribution of HB and RA are not described except for patient IV-8.
CasePresentingHPOs: HP:0002666 (Pheochromocytoma)
CaseHPOFreeText: N/A
CaseNotHPOs: HP:0005584 (Renal cell carcinoma)
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: 7759077
SupplementalData: N/A
Variant: p.Y98H (c.292T>C)
LegacyVariant: N/A
CaseProblemVariantFreeText: N/A
ClinVarID: 2223, https://www.ncbi.nlm.nih.gov/clinvar/variation/2223/
CAID: N/A
gnomAD: 0.00001343, https://gnomad.broadinstitute.org/variant/3-10183823-T-C
VariantEvidence: N/A
MutationType: missense_variant;transition
CivicName: Y98H (c.292T>C)
MultipleGeneVariants: N/A
PatientID: V-37
KindredID: 2
Case: F, Age Unknown, German
DiseaseAssertion: VHL
FamilyInfo: Family 2 is comprised of 131 individuals over six generations including 65 members (50% of those at risk) with VHL type 2A (72% clinically affected, 12% obligate carriers, and 15% positive genetic analysis alone) and nearly equal gender distribution for affected status (54% male). An additional six members (II-3, II-4, II -5, III-1, III-2, and III-3) are suspected to have VHL without confirmation. Of note, the nuclear family (branch IV-13) contains 13 siblings, of whom 12 have been diagnosed with pheo. The presenting tumor types in Family 2 were pheo (70%), HB (17%), and RA (13%). No Family 2 member had RCC as the initial manifestation. Distribution of HB and RA are not described except for patient IV-8.
CasePresentingHPOs: HP:0002666 (Pheochromocytoma)
CaseHPOFreeText: N/A
CaseNotHPOs: HP:0005584 (Renal cell carcinoma)
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: 7759077
SupplementalData: N/A
Variant: p.Y98H (c.292T>C)
LegacyVariant: N/A
CaseProblemVariantFreeText: N/A
ClinVarID: 2223, https://www.ncbi.nlm.nih.gov/clinvar/variation/2223/
CAID: N/A
gnomAD: 0.00001343, https://gnomad.broadinstitute.org/variant/3-10183823-T-C
VariantEvidence: N/A
MutationType: missense_variant;transition
CivicName: Y98H (c.292T>C)
MultipleGeneVariants: N/A
PatientID: V-24
KindredID: 2
Case: F, Age Unknown, German
DiseaseAssertion: VHL
FamilyInfo: Family 2 is comprised of 131 individuals over six generations including 65 members (50% of those at risk) with VHL type 2A (72% clinically affected, 12% obligate carriers, and 15% positive genetic analysis alone) and nearly equal gender distribution for affected status (54% male). An additional six members (II-3, II-4, II -5, III-1, III-2, and III-3) are suspected to have VHL without confirmation. Of note, the nuclear family (branch IV-13) contains 13 siblings, of whom 12 have been diagnosed with pheo. The presenting tumor types in Family 2 were pheo (70%), HB (17%), and RA (13%). No Family 2 member had RCC as the initial manifestation. Distribution of HB and RA are not described except for patient IV-8.
CasePresentingHPOs: HP:0002666 (Pheochromocytoma)
CaseHPOFreeText: N/A
CaseNotHPOs: HP:0005584 (Renal cell carcinoma)
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: 7759077
SupplementalData: N/A
Variant: p.Y98H (c.292T>C)
LegacyVariant: N/A
CaseProblemVariantFreeText: N/A
ClinVarID: 2223, https://www.ncbi.nlm.nih.gov/clinvar/variation/2223/
CAID: N/A
gnomAD: 0.00001343, https://gnomad.broadinstitute.org/variant/3-10183823-T-C
VariantEvidence: N/A
MutationType: missense_variant;transition
CivicName: Y98H (c.292T>C)
MultipleGeneVariants: N/A
Partial deletions were heterozygous in size and position: one removed exon 3
PatientID: 14
KindredID: 14
Case: M, 51Y0M, Korean
DiseaseAssertion: VHL
FamilyInfo: None
CasePresentingHPOs: HP:0010797; HP:0005584 (hemangioblastoma, renal cell carcinoma)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: Previously reported, HGMD (Human Gene Mutation Database) [Refer to table 2].
SupplementalData: N/A
Variant: Exon 3 deletion (c.464-?_642+?del)
CaseProblemVariantFreeText: N/A
LegacyVariant: N/A
ClinVar: N/A
CAID: N/A
gnomAD: N/A
VariantEvidence: N/A
MutationType: exon_loss_variant
CivicName: Exon 3 deletion
MultipleGeneVariants: N/A
Multiplex ligation-dependent probe amplification (MLPA) analysis of VHL exons 1-3. Signal intensity reveals only a single copy of VHL exon 2 and 3 in a patient with VHL due to deletion of VHL exon 2 and 3 (A) and only a single copy of each VHL exon in a patient with VHL due to deletion of whole VHL gene deletion (B) when compared to a healthy control (C).
PatientID: None (sister)
KindredID: 10
Case: F, 38Y0M, Korean
DiseaseAssertion: VHL
FamilyInfo: Patient had a positive family history: Her father was died of RCC (no mutation availible), and her older sister who presented with spinal HB and multiple cysts in pancreas and both kidneys, harbored the same exon deletion
CasePresentingHPOs: HP:0010797; HP:0005584 (hemangioblastoma, renal cell carcinoma)
CaseHPOFreeText: presented with medullary HB at the age of 37 and multiple RCC in both kidneys at the age of 38
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: N/A
Variant: Exon 1-3 deletion (c.1-?_642+?del)
CaseProblemVariantFreeText: N/A
LegacyVariant: N/A
ClinVar: N/A
CAID: N/A
gnomAD: N/A
VariantEvidence: N/A
MutationType: exon_loss_variant
CivicName: Exon 1-3 Deletion
MultipleGeneVariants: N/A
detected point germline vhl mutations in 14 patients
PatientID: 20
KindredID: 20
Case: 19Y0M, sex unknown, ethnicity unknown
DiseaseAssertion: VHL
FamilyInfo: N/A
CasePresentingHPOs: HP:0010797; HP:0009711 (hemangioblastoma; retinal capillary hemangioma)
CaseHPOFreeText: See Table 1&2 for retinal capillary hemangioma information
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: N/A
Variant: p.Y98N (c.292T>A)
CaseProblemVariantFreeText: N/A
LegacyVariant: N/A
ClinVarID: N/A
CAID: CA351750883 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.292T%3EA
gnomAD: N/A
VariantEvidence: N/A
MutationType: missense_variant; transversion
CivicName: Y98N (c.292T>A)
MultipleGeneVariants: N/A
Table 1
PatientID: N/A
KindredID: 10
Case: Sex Unknown, Age Unknown, Ethnicity Unknown
DiseaseAssertion: VHL
FamilyInfo: Family history not mentioned. Patient’s variant reported as germline.
CasePresentingHPOs: HP:0002666; HP:0005584; HP:0010797; HP:0009711; HP:0030424 (pheochromocytoma, renal cell carcinoma, hemangioblastoma, retinal capillary hemangioma, epididymal cyst)
CaseHPOFreeText: Patient had VHL disease, RCC, CNS-HB, R-HB, PH, and epididymal cyst (see table 1)
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: 17661816; HGMD (Human Gene Mutation Database: http://uwcmml1s.uwcm.ac.uk/uwcm/mg/search/120488.html)
SupplementalData: N/A
Variant: p.F76del (c.227_229del)
LegacyVariant: N/A
CaseProblemVariantFreeText: N/A
ClinVarID: N/A
CAID: CA357012, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.227_229delTCT
gnomAD: N/A
VariantEvidence: N/A
MutationType: inframe_deletion
CivicName: F76del (c.227_229del)
MultipleGeneVariants: N/A
Eighteen VHL patients who underwent pancreatectomy for one or several endocrine tumors at Beaujon hospital from 1997 to 2008 were retrieved from the file of VHL patients (Table 1).
Eighteen VHL patients who underwent pancreatectomy for one or several endocrine tumors at Beaujon hospital from 1997 to 2008 were retrieved from the file of VHL patients. All patients had VHL germline mutations. Age is at the time of surgery. Patients #2 (female) and #12 (male) were found with this germline VHL mutation and pancreatic endocrine tumours. The last known age of the patients was 28Y, and 43Y respectively. Other phenotypes and demographics were unknown. ACMG PP4
Eighteen VHL patients who underwent pancreatectomy for one or several endocrine tumors at Beaujon hospital from 1997 to 2008 were retrieved from the file of VHL patients (Table 1).
PatientID: 12
KindredID: 12
Case: M, 43Y0M, Ethnicity unknown
DiseaseAssertion: pancreatic endocrine tumor
FamilyInfo: None
CasePresentingHPOs: HP:0030405 (pancreatic endocrine tumor)
CaseHPOFreeText: See Table 1 for more information
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: N/A
Variant: p.R167W (c.499C>T)
CaseProblemVariantFreeText: N/A
LegacyVariant: N/A
ClinVarID: 2218 https://www.ncbi.nlm.nih.gov/clinvar/variation/2218/
CAID: CA020450 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.499C%3ET
gnomAD: 0.000007954 https://gnomad.broadinstitute.org/variant/3-10191506-C-T?dataset=gnomad_r2_1
VariantEvidence: N/A
MutationType: missense_variant; transition
CivicName: R167W (c.499C>T)
MultipleGeneVariants: N/A
56 male patients age 12 to 76 years, from 40 families with VHL were examined as part of a larger screening program for VHL. VHL mutations were identified in 16 families. Individual patient phenotype-genotype data was not available, but the mutations found and whether the corresponding patient had epididymal cystadenoma (EC) was reported. A p.E186* (c.556G>T) VHL mutation was found in a VHL patient without EC. This mutation was referred to in the paper as c.769G>T due to a difference in transcript sequence.
56 male patients age 12 to 76 years, from 40 families with VHL were examined as part of a larger screening program for VHL. VHL mutations were identified in 16 families. Individual patient phenotype-genotype data was not available, but the mutations found and whether the corresponding patient had epididymal cystadenoma (EC) was reported. A c.180delG VHL mutation was found in a VHL patient without EC. This mutation was referred to in the paper as c.393delG due to a difference in transcript sequence.
Biochemically normal adrenal pheochromocytoma following extensive central necrosis in a child with von Hippel-Lindau (VHL) gene mutation
PMID: 34937752
Gene: VHL
StandardizedReferenceSequence: NM_000551.3
VHL_17FFPEc.523T>Ap.Tyr175AsnM12AdrenalPCCB
PatientID: VHL_17 (tumor ID)
KindredID: 17
Case: M, 12Y0M, Ethnicity Unknown
DiseaseAssertion: Adrenal pheochromocytoma
FamilyInfo: N/A
CasePresentingHPOs: HP:0006748 (Adrenal pheochromocytoma)
CaseHPOFreeText: The patient had a benign adrenal pheochromocytoma at 12Y.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: N/A
Variant: p.Y175N (c.523T>A)
LegacyVariant: N/A
CaseProblemVariantFreeText: N/A
ClinVarID: N/A
CAID: CA351756226, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.523T%3EA
gnomAD: N/A
VariantEvidence: N/A
MutationType: missense_variant;transversion
CivicName: Y175N (c.523T>A)
MultipleGeneVariants: N/A
PatientID: None (Daughter)
KindredID: 12
Case: F, Age Unknown, Korean
DiseaseAssertion: VHL
FamilyInfo: Mother has the same mutation and presented with renal cell caricnoma.
CohortInfo: 26 Korean patients with more than one HAB in the CNS or eye, a single HAB in the CNS or retina plus a visceral manifestation (multiple renal, pancreatic or hepatic cysts, pheochromocytoma and RCC) and positive family history plus any one of the above manifestations.
CasePresentingHPOs: HP:0010797 (Hemangioblastoma)
CaseHPOFreeText: CNS hemangioblastoma. Diagnosed with VHL Type 1.
CaseNotHPOs: HP:0005584; HP:0002666; HP:0009711 (Renal cell carcinoma, Pheochromocytoma, Retinal capillary hemangioma)
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: N/A
Variant: p.Q73* (c.217C>T)
LegacyVariant: N/A
CaseProblemVariantFreeText: N/A
ClinVarID: 223164, https://www.ncbi.nlm.nih.gov/clinvar/variation/223164/
CAID: N/A
gnomAD: N/A
VariantEvidence: N/A
MutationType: missense_variant;transition; stop_gained
CivicName: Q73* (c.217C>T)
MultipleGeneVariants: N/A
Medical records of 26 patients with germline mutations of the VHL gene who had been diagnosed with VHL disease in Severance Hospital (Seoul, Republic of Korea) and Samsung Medical Center (Seoul, Republic of Korea) between 2003 and 2012 were reviewed. Peripheral blood leukocytes were isolated and directly sequenced. 1 patient presented with the c.250G>T/p.Val84Leu germline variant of the VHL gene. Patient 16, 60Y female previously published in PMID 16142346, presented with multiple pheochromocytomas and a positive family history for VHL. She was diagnosed with VHL Type 2C.
Medical records of 26 patients with germline mutations of the VHL gene who had been diagnosed with VHL disease in Severance Hospital (Seoul, Republic of Korea) and Samsung Medical Center (Seoul, Republic of Korea) between 2003 and 2012 were respectively reviewed. Three unrelated probands were genetically confirmed with a germline missense mutation at c.499C>T of the VHL gene. Patients 42 and 44, 10Y and 30Y males respectively, both presented with multiple and/or bilateral pheochromocytoma and CNS hemangioblastomas. Patient 43, 30Y male, presented with multiple and/or bilateral pheochromocytoma and retinal hemangioblastoma. Patients 42 and 43 had a family history negative for VHL disease while patient 44 had a positive family history of VHL disease. Patient 43s phenotypes were revised from a previous report (PMID 19949673). Patient 44 was previously reported in PMID 16142346 as well as Kim et al., 2005 (reference 15 in the current paper). All of these patients were diagnosed with VHL Type 2A.
Bilateral renal tumors; conventional clear cell carcinoma and contralateral t(6;11)/t(X;17)-like tumor Histomorphologic, immunohistochemical, ultrastructural and molecular genetic studies including the report of a novel mutation in the VHL gene
PMID: 20952280
Gene: VHL
StandardizedReferenceSequence: NM_000551.3
GroupID/ KindredID: 15
DiseaseAssertion: pheochromocytoma
GroupSize: 2
GroupNumberMales: N/A
GroupNumberFemales: N/A
GroupEthnicity: N/A
GroupAgeRange: N/A
GroupInfo: 2 patients are listed with this mutation; any relation is unknown. This mutation was said to be spontaneous.
GroupPresentingHPOs: HP:0002666 (pheochromocytoma)
GroupHPOFreeText: 2 members are stated to have pheochromocytoma. Other manifestations are possible but not clear.
GroupNotHPOs: N/A
GroupNotHPOFreeText: N/A
GroupPreviousTesting: RET, SDHB, SDHD
PreviouslyPublished: N/A
SupplementalData: N/A
Variant: p.R161Q (c.482G>A)
CaseProblemVariantFreeText: N/A
LegacyVariant: p.R161Q (c.695G>A)
ClinVarID: 182983 https://www.ncbi.nlm.nih.gov/clinvar/variation/182983/
CAID: N/A
gnomAD: N/A
VariantEvidence: N/A
MutationType: missense_variant; transition
CivicName: R161Q (c.482G>A)
MultipleGeneVariants: N/A
GroupID/ KindredID: VHL 7
DiseaseAssertion: assumed VHL
GroupSize: 3
GroupNumberMales: N/A
GroupNumberFemales: N/A
GroupEthnicity: Croatian
GroupAgeRange: N/A
GroupInfo: 3 patients with the given mutation belonging to VHL family 7
GroupPresentingHPOs: HP:0009711; HP:0010797; HP:0000107; HP:0001737 (retinal capillary hemangioma, hemangioblastoma, renal cyst, pancreatic cysts)
GroupHPOFreeText: all 3 patients has retinal capillary hemangiomas, but only 1 tally of hemangioblastomas of the central nervous system, renal cysts, and pancreatic cysts were listed.
GroupNotHPOs: N/A
GroupNotHPOFreeText: N/A
GroupPreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: N/A
Variant: c.463+2T>C
CaseProblemVariantFreeText: The mutation was referred to in the paper as c.676+2C>T - which was corrected to c.676+2T>C with a footnote indicating the correction in relation to Glavac et al Hum Mutat 1996.
LegacyVariant: c.676+2C>T (or correction of c.676+2T>C)
ClinVarID: 569414 https://www.ncbi.nlm.nih.gov/clinvar/variation/569414/
CAID: N/A
gnomAD: N/A
VariantEvidence: N/A
MutationType: splice_site_variant
CivicName: Splice Site (c.463+2T>C)
MultipleGeneVariants: N/A
PatientID: 220
KindredID: 82
Case: M, 36Y0M, Chinese
DiseaseAssertion: VHL
FamilyInfo: The proband's mother and sister both presented with renal cell carcinoma at ages 49 and 27, respectively. Their mother also had a CNS hemangioblastoma at 45, and their sister had a retinal angioma at 30. No genotyping information was available for either family member.
CasePresentingHPOs: HP:0005584; HP:0002666 (Renal cell carcinoma, Pheochromocytoma)
CaseHPOFreeText: The proband presented with renal cell carcinoma at age 22, and a pheochromocytoma at age 36.
CaseNotHPOs: HP:0009711; HP:0001737; HP:0001732; HP:0010797 (Retinal capillary hemangioma, Pancreatic cysts, Abnormality of the pancreas, Hemangioblastoma)
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: This cohort was also published in a later paper by Wang et al., 2018 (PMID: 29330336).
SupplementalData: Patient and family genotype-phenotype information is listed in Supplementary Table 1.
Variant: p.R167Q (c.500G>A)
LegacyVariant: N/A
CaseProblemVariantFreeText: N/A
ClinVarID: 2216, https://www.ncbi.nlm.nih.gov/clinvar/variation/2216/
CAID: N/A
gnomAD: N/A
VariantEvidence: N/A
MutationType: missense_variant;transition
CivicName: R167Q (c.500G>A)
MultipleGeneVariants: N/A
PatientID: 81
KindredID: 27
Case: M, 38Y0M, Chinese
DiseaseAssertion: VHL
FamilyInfo: The proband (patient 81) had 3 family members confirmed with the mutation: his aunt 2 (patient 85) had pancreatic cysts and/or tumors at age 50, his cousin/ the son of Aunt 2 was asymptomatic at the time of assessment, and the granddaughter of aunt 2 was also asymptomatic at the time of assessment. The proband also had 3 family members who passed away before diagnosis/ before confirming the mutation: his mother (patient 82) had a CNS hemangioblastoma at 33, his Aunt 1 (patient 83) had a CNS hemangioblastoma at 32, and his cousin/ the son of Aunt 1 (patient 84) had a CNS hemangioblastoma at 30.
CasePresentingHPOs: HP:0010797; HP:0001732; HP:0001737; HP:0005584; HP:0002666 (Hemangioblastoma, Abnormality of the pancreas, Pancreatic cysts, Renal cell carcinoma, Pheochromocytoma)
CaseHPOFreeText: The proband presented with CNS hemangioblastoma at age 28, and renal cell carcinoma, multiple pancreatic cysts/tumors, and pheochromocytoma at age 38.
CaseNotHPOs: HP:0009711(Retinal capillary hemangioma)
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: This patient was also published in a later paper by Wang et al., 2018 (PMID: 29330336).
SupplementalData: Patient and family genotype-phenotype information is listed in Supplementary Table 1.
Variant: p.N90I (c.269A>T)
LegacyVariant: N/A
CaseProblemVariantFreeText: N/A
ClinVarID: 223172; https://www.ncbi.nlm.nih.gov/clinvar/variation/223172/
CAID: N/A
gnomAD: N/A
VariantEvidence: N/A
MutationType: missense_variant;transversion
CivicName: N90I (c.269A>T)
MultipleGeneVariants: N/A
PatientID: 160
KindredID: 61
Case: M, 44Y0M, Chinese
DiseaseAssertion: VHL
FamilyInfo: N/A
CasePresentingHPOs: HP:0005584 (Renal cell carcinoma)
CaseHPOFreeText: The proband presented with a renal cell carcinoma at age 44.
CaseNotHPOs: HP:0009711; HP:0002666; HP:0010797; HP:0001737; HP:0001732 (Retinal capillary hemangioma, Pheochromocytoma, CNS Hemangioblastoma, Pancreatic cysts, Abnormality of the pancreas)
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: This cohort was also published in a later paper by Wang et al., 2018 (PMID: 29330336).
SupplementalData: Patient and family genotype-phenotype information is listed in Supplementary Table 1.
Variant: p.R161* (c.481C>T)
LegacyVariant: N/A
CaseProblemVariantFreeText: N/A
ClinVarID: 2217, https://www.ncbi.nlm.nih.gov/clinvar/variation/2217/
CAID: N/A
gnomAD: N/A
VariantEvidence: N/A
MutationType: missense_variant;transition
CivicName: R161* (c.481C>T)
MultipleGeneVariants: N/A
217C→T Ts Exon 1 73 CAG Q Q73X
GroupID: 8
DiseaseAssertion: VHL
GroupSize: 5
GroupNumberMales: N/A
GroupNumberFemales: N/A
GroupEthnicity: French
GroupAgeRange: N/A
GroupInfo: 5 patients are listed with this mutation; any relation is unknown.
GroupPresentingHPOs: HP:0009711 (retinal capillary hemangioma)
GroupHPOFreeText: 4 members are said to have retinal HBs. Other manifestations are not clearly stated.
GroupNotHPOs: HP:0009711 (retinal capillary hemangioma)
GroupNotHPOFreeText: the other member is specifically said to not have retinal HBs
GroupPreviousTesting: N/A
PreviouslyPublished: Possibly published in PMID:15300849
SupplementalData: N/A
Variant: p.Q73* (c.217C>T)
CaseProblemVariantFreeText: N.A
LegacyVariant: N/A
ClinVarID: 223164 https://www.ncbi.nlm.nih.gov/clinvar/variation/223164/
CAID: N/A
gnomAD: N/A
VariantEvidence: N/A
MutationType: stop_gained
CivicName: Q73* (c.217C>T)
MultipleGeneVariants: N/A
351G→T Tv Exon 2 117 TGG W W117C
GroupID: 27
DiseaseAssertion: VHL
GroupSize: 5
GroupNumberMales: N/A
GroupNumberFemales: N/A
GroupEthnicity: French
GroupAgeRange: N/A
GroupInfo: 5 patients are listed with this mutation; any relation is unknown.
GroupPresentingHPOs: HP:0009711 (retinal capillary hemangioma)
GroupHPOFreeText: 4 members are said to have retinal HBs. Other manifestations are not clearly stated.
GroupNotHPOs: HP:0009711 (retinal capillary hemangioma)
GroupNotHPOFreeText: the other 1 member is specifically said to not have retinal HBs
GroupPreviousTesting: N/A
PreviouslyPublished: Possibly published in PMID:15300849
SupplementalData: N/A
Variant: p.W117C (c.351G>T)
CaseProblemVariantFreeText: N.A
LegacyVariant: N/A
ClinVarID: 167827 https://www.ncbi.nlm.nih.gov/clinvar/variation/167827/
CAID: N/A
gnomAD: N/A
VariantEvidence: N/A
MutationType: missense_variant; transversion
CivicName: W117C (c.351G>T)
MultipleGeneVariants: N/A
467A→G Ts Exon 3 156 TAT Y Y156C
GroupID: 38
DiseaseAssertion: VHL
GroupSize: 3
GroupNumberMales: N/A
GroupNumberFemales: N/A
GroupEthnicity: French
GroupAgeRange: N/A
GroupInfo: 3 patients are listed with this mutation; any relation is unknown.
GroupPresentingHPOs: HP:0009711 (retinal capillary hemangioma)
GroupHPOFreeText: 1 member is said to have retinal HBs. Other manifestations are not clearly stated.
GroupNotHPOs: HP:0009711 (retinal capillary hemangioma)
GroupNotHPOFreeText: the other 2 members are specifically said to not have retinal HBs
GroupPreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: N/A
Variant: p.Y156C (c.467A>G)
CaseProblemVariantFreeText: N.A
LegacyVariant: N/A
ClinVarID: 43600 https://www.ncbi.nlm.nih.gov/clinvar/variation/43600/
CAID: N/A
gnomAD: N/A
VariantEvidence: N/A
MutationType: missense_variant; transtition
CivicName: Y156C (c.467A>G)
MultipleGeneVariants: N/A
VHL{"type":"entrez-nucleotide","attrs":{"text":"NM_000551.4","term_id":"1779521775"}}NM_000551.4:c.481C>Tp.(Arg161Ter)rs5030818
75 individuals pre-diagnosed with pheochromocytoma and/or paraganglioma were referred for molecular genetic testing. Genomic DNA of each participant was isolated from peripheral blood samples to look for germline mutations in pheochromocytoma and paraganglioma targeted susceptibility genes. 6 targeted genes (IF1B, RET, SDHB, SDHD, TMEM127, and VHL) were sequenced and identified variants were confirmed by sanger sequencing. Patient 2 was pre-diagnosed with bilateral pheochromocytoma and sequencing identified a germline R161*(c.481C>T) nonsense variant in the VHL gene. Patient 2 had two affected family members, his father and sister. It does not describe how they were affected nor any diagnosis or variant.
Missense mutation in codon 78, exon 1, asparagine to aspartic acid substitution
Of 14 patients with retinal vascular proliferation and known family history of VHL disease, 12 patients were enrolled in an approved study protocol at the National Cancer Institute. 11 of these patients underwent genetic testing and were found to have mutations in the VHL gene. Patient 6, age 34, had retinal vascular proliferation, CNS hemangioblastoma, pancreatic and renal abnormalities, and an epididymal cyst. She was found to carry the N78D (c.232A>G) mutation. ACMG evidence codes: 'PP4' since the patient presents phenotypes highly specific for a disease with a single genetic etiology.
c.394 C>Tap.Q132X
GroupID: 14A
Case: Sex, Age, Ethnicity unknown
DiseaseAssertion: VHL
FamilyInfo: None. The patient with the given mutation in this study was a VHL patient with pancreatic ICTs.
CasePresentingHPOs: HP:0030405 (pancreatic endocrine tumor)
CaseHPOFreeText: Patient has islet cell tumors (ICTs), or listed as pancreatic endocrine tumor.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: N/A
Variant: p.Q132* (c.394C>T)
LegacyVariant: N/A
CaseProblemVariantFreeText: N/A
ClinVarID: 288749 https://www.ncbi.nlm.nih.gov/clinvar/variation/288749/
CAID: N/A
gnomAD: N/A
VariantEvidence: N/A
MutationType: stop_gained
CivicName: Q132* (c.394C>T)
MultipleGeneVariants: N/A
c.277 G>Cap.G93R
53 patients with a molecularly confirmed VHL mutation (by PCR through EDTA-anticoagulated blood) and a pancreatic neuroendocrine tumor (ICT) were collected from the German NET-Registry and the German VHL-registry. An additional 296 patients were stated in this paper with a VHL associated germline mutation, but without pancreatic neuroendocrine tumors. 1 patient was found to have the above mutation (c.277G>C). Other clinical manifestations outside of a pancreatic neuroendocrine tumor are possible, but were not discussed. ACMG evidence codes: 'PP2' because they observe a missense variant in a gene where missense variants are a common mechanism of disease.
All registrants provided 10 ml EDTA-anticoagulated blood for molecular genetic analyses. The analyses comprised testing of all exons including the splice sites of the VHL (RefSeq:NM_000551.2) and MEN1 (RefSeq:NM_130803.1) genes for germline mutations. DNA extraction, primers, PCR conditions, and sequencing methods followed published protocols of international standards (Lemmens et al. 1997, Franke et al. 2009). The primers are available on request. Of note, analyses also included screening for large deletions or rearrangements of the VHL and MEN1 genes. For screening for intragenic mutations, we used the PCR-based denaturing HPLC. For detection of large deletions/rearrangements, we used two commercially available kits for multiplex ligation-dependent probe amplification, the SALSA MLPA KIT P016 VHL, and the SALSA MLPA KIT P017-B1 MEN1 respectively (MLPA, MRC Holland, Amsterdam, The Netherlands). The primers are available on request. All analyses for the VHL gene and the analyses for intragenic mutations in the MEN1 gene have been performed in Freiburg. The analyses for the large deletions and rearrangements of the MEN1 gene have been performed in Madrid.
ArticleReferenceSequence: NM_000551.2
GenotypingMethod: PCR; and the SALSA MLPA KIT P016 VHL for detection of large deletions/rearrangements.
SamplingMethod: blood (EDTA-anticoagulated blood).
Pancreatic serous cystadenocarcinoma in von hippel-lindau disease.
PMID: N/A
OVID: 613520271
Reference: Sirinvaravong S., Boonsaen T. & Wannachalee T. (2016). Pancreatic serous cystadenocarcinoma in von hippel-lindau disease. Endocrine Reviews, 37(2 Supplement 1), no pagination. https://doi.org/10.1210/endo-meetings.2016.TB.9.SAT-076
Gene: VHL
StandardizedReferenceSequence: NM_000551.3
Somatic mosaicism in von Hippel-Lindau Disease
PMID: 10612832
Gene: VHL
StandardizedReferenceSequence: NM_000551.3
c.523T>A
This paper describes the clinical and genetic findings of 36 Spanish pediatric patients with pheochromocytoma or paraganglioma. Genetic testing involved sequencing and MLPA of VHL, RET, SDHA, SDHB, SDHC, SDHD, SDHAF2, TMEM127, and MAX. The molecular analysis identified 8 patients with variants in the VHL gene. The missense mutation, c.523T>A, was found in patient 12, a 13 year old-male patient who had thoracic-abdominal paraganglioma (onset age 12) and pheochromocytoma (onset age 13).
nt 443 Ins.TCT 77 Ins. Leu 443ins3 In-frame ins 1
A cohort of 141 patients with hemangioblastomas of the central nervous system was analyzed. 81 patients had germline mutations in the VHL gene, analyzed through peripheral blood by Southern blotting and SSCP analysis. This inframe mutation (c.230_231insTCT) was recorded in the paper as c.443insTCT due to a difference in transcript sequence. It was found in 1 patient with a hemangioblastoma of the central nervous system. Any family information is unknown. No other phenotypes described.
nt 694 C/G 161 Arg→Gly R161G Missense 1
PatientID: 31
GroupID/ KindredID: 31
Case: Sex Unknown, Age Unknown, Ethnicity Unknown
DiseaseAssertion: hemangioblastoma
FamilyInfo: N/A
CasePresentingHPOs: HP:0010797 (hemangioblastoma)
CaseHPOFreeText: other phenotypes unknown.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: N/A
Variant: p.R161G (c.481C>G)
LegacyVariant: p.R161G (c.694C>G)
CaseProblemVariantFreeText: N/A
ClinVarID: 618484 https://www.ncbi.nlm.nih.gov/clinvar/variation/618484/
CAID: N/A
gnomAD: N/A
VariantEvidence: N/A
MutationType: missense_variant; transversion
CivicName: R161G (c.481C>G)
MultipleGeneVariants: N/A
VHL kindreds for germline mutations and calculated the age related tumour risks for different classes of VHL gene mutations.
PatientID: None
KindredID: 36
Case: Age, sex ethnicity unknown
DiseaseAssertion: unknown; paper focused only on pheochromocytoma
FamilyInfo: No specific family info was present; although this was recorded as a family germline mutation belonging to Family ID 36
CasePresentingHPOs: N/A
CaseHPOFreeText: Unknown
CaseNotHPOs: HP:0002666 (pheochromocytoma)
CaseNotHPOFreeText: No presence of phaeochromocytoma in family
CasePreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: N/A
Variant: p.R177* (c.529A>T)
CaseProblemVariantFreeText: N/A
LegacyVariant: p.R177* (c.742A>T)
ClinVarID: 625258 https://www.ncbi.nlm.nih.gov/clinvar/variation/625258/
CAID: N/A
gnomAD: N/A
VariantEvidence: N/A
MutationType: stop_gained
CivicName: R177* (c.529A>T)
MultipleGeneVariants: N/A
germline missense mutation at nucleotide 505 (T to C) of the VHL tumor suppressor gene in 14, apparently unrelated, VHL type 2A families from the Black Forest region of Germany.
GroupID/ KindredID: VHL 16
DiseaseAssertion: assumed VHL
GroupSize: 4
GroupNumberMales: N/A
GroupNumberFemales: N/A
GroupEthnicity: German
GroupAgeRange: N/A
FamilyInfo: 4 affected members belong to this VHL type 2A family. One representative affected member was analyzed with this mutation, and VHL was diagnosed clinically in this index person. It is unclear as to whether the additional patients had this precise mutation, although assumed.
GroupPresentingHPOs: HP:0009711; HP:0002666; HP:0010797 (retinal capillary hemangioma, pheochromocytoma, hemangioblastoma)
GroupHPOFreeText: 3 individuals had Pheos, 3 had retinal capillary hemangiomas, but only 1 had a CNS hemangioblastoma.
GroupNotHPOs: HP:0005584; HP:0001737; HP:0009715 (renal cell carcinoma, pancreatic cysts, papillary cystadenoma of the epididymis)
GroupNotHPOFreeText: No patients had the above tumors
GroupPreviousTesting: N/A
PreviouslyPublished: 11134110, 9681856, 11850829
SupplementalData: N/A
Variant: p.Y98H (c.292T>C)
LegacyVariant: p.Y98H (c.505T>C)
CaseProblemVariantFreeText: N/A
ClinVar: 2223 https://www.ncbi.nlm.nih.gov/clinvar/variation/2223/
CAID: N/A
gnomAD: 0.00001343 https://gnomad.broadinstitute.org/variant/3-10183823-T-C
VariantEvidence: N/A
MutationType: missense_variant;transition
CivicName: Y98H (c.292T>C)
MultipleGeneVariants: N/A
Analysis of protein structure The same missense substitution may be pathogenic or neutral depending on the location of the amino acid change within the encoded protein. Substitutions at sites that are important for structure or function of the encoded protein are more likely to be pathogenic. In fact, up to three-quarters of the missense variants responsible for human monogenic diseases may destabilize protein structure.20 The VHL protein (pVHL) is the substrate recognition component in a ternary complex with Elongin B and Elongin C, responsible for regulation of hypoxia inducible factor (HIF).21 Studies of the pVHL quaternary structure show that Asp121 is folded into the beta domain hydrophobic core, a relatively buried site that is not directly important for Elongin C binding. However, polar residues in the beta domain core are structurally important and substitutions here have the potential to cause complete unravelling of pVHL.22 Substitutions of Asp121 are not a frequent cause of VHL but there are two that have been demonstrated to be pathogenic: the switch of aspartic acid for asparagine (Asp121Asn) and the switch of aspartic acid for glycine (Asp121Gly).8
PatientID: 3
KindredID: 3
Case: M, 60Y0M, Ethnicity Unknown
DiseaseAssertion: VHL
FamilyInfo: It is stated that the eight VHL patients were selected from the group of familial VHL patients. Assuming there is family history.
CohortInfo: Eight patients with VHL disease with pheochromocytoma, eight patients with MEN2 and pheochromocytoma, and 10 sporadic patients.
CasePresentingHPOs: HP:0006748, HP:0010797, HP:0005584, HP:0030405, HP:0009711, HP:0030393 (adrenal pheochromocytoma, hemangioblastoma, renal cell carcinoma, pancreatic endocrine tumour, retinal capillary hemangioma, endolymphatic sac tumor)
CaseHPOFreeText: The patient had a right adrenal pheochromocytoma at age 35. The patient had two pheochromocytomas.
CaseNotHPOs: HP:0008221 (Adrenal hyperplasia)
CaseNotHPOFreeText: The patient did not have adrenomedullary hyperplasia.
CasePreviousTesting: N/A
PreviouslyPublished: Suspected to be, but not mentioned in paper. Paper says, the eight VHL patients were selected from the group of familial VHL patients withknown VHL germline mutations followed on a clinical protocol at the Urologic Oncology Branch, National Cancer Institute, National Institutes of Health (NIH).
SupplementalData: N/A
Variant: p.C162W (c.486C>G)
LegacyVariant: p.C162W (c.699C>G)
CaseProblemVariantFreeText: N/A
ClinVarID: 223227 https://www.ncbi.nlm.nih.gov/clinvar/variation/223227/
CAID: N/A
gnomAD: N/A
VariantEvidence: N/A
MutationType: missense_variant; transversion
CivicName: C162W (c.486C>G)
MultipleGeneVariants: N/A
c.533T>G p.Leu178Arg
PatientID: None (proband 10)
KindredID: 10
Case: M, 57Y0M, Chinese
DiseaseAssertion: VHL
FamilyInfo: Patient’s son was found with the same mutation, as well as RCC diagnosed at 30Y
CasePresentingHPOs: HP:0010797; HP:0009711; HP:0005584; HP:0001737 (hemangioblastoma, retinal capillary hemangioma, renal cell carcinoma, pancreatic cysts)
CaseHPOFreeText: patient had hemangioblastoma diagnosed at 39Y, as well as retinal capillary hemangioma, renal cell carcinoma and pancreatic cysts diagnose at 57Y
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: N/A
Variant: p.L178R (c.533T>G)
CaseProblemVariantFreeText: N/A
LegacyVariant: N/A
ClinVarID: 625261 https://www.ncbi.nlm.nih.gov/clinvar/variation/625261/
CAID: N/A
gnomAD: N/A
VariantEvidence: N/A
MutationType: missense_variant; transversion
CivicName: L178R (c.533T>G)
MultipleGeneVariants: N/A
c.499C>T p.Arg167Trp
During the period from 2009 to 2012, 39 families with VHL disease were diagnosed with hereditary VHL disease at Peking University First Hospital Department of Urology were described as part of a broader study examining telomere length and anticipation. In these families, 19 families had two or more than two patients in two or more than two generations, including one family with obscure onset age. Therefore, a total of 57 patients with VHL disease from 18 families were enrolled in this study. Using peripheral blood and southern blotting, DNA sequencing was completed on the following patients. Family 5 involved four members with a c.499C>T change leading to a p.Arg167Trp protein change. The first member, the father, presented with renal cell carcinoma at 63. His 3 daughters also presented. The first daughter presented with hemangioblastoma, renal cell carcinoma, ovarian cyst, and pancreatic cysts at 37, as well as pheochromocytoma at 39. The second daughter presented with pancreatic cysts at 36 and hemangioblastoma at 38. The third presented with retinal capillary hemangioma at 34. The first born son did not present with any symptoms nor the mutation. ACMG Evidence Code: 'PP4' because the patients' phenotypes and family histories are highly specific for VHL disease.
c.349T>G p.Trp117Gly
PatientID: III:7
KindredID: 7
Case: M, 13Y0M, Chinese
DiseaseAssertion: VHL
FamilyInfo: 8 other members of this 3 generation family were observed to be affected with various presentations of VHL. This patient’s father and 3 cousins were confirmed with identical mutations. DNA samples were not available for all members in the family however.
CasePresentingHPOs: HP:0010797 (hemangioblastoma)
CaseHPOFreeText: had hemangioblastoma at 13Y
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: N/A
Variant: p.W117G (c.349T>G)
CaseProblemVariantFreeText: N/A
LegacyVariant: N/A
ClinVarID: 862346 https://www.ncbi.nlm.nih.gov/clinvar/variation/862346/
CAID: N/A
gnomAD: N/A
VariantEvidence: N/A
MutationType: missense_variant;transversion
CivicName: W117G (c.349T>G)
MultipleGeneVariants: N/A
This study reports 1,548 germline and somatic mutations from 945 VHL families, including 30 previously unpublished kindreds from The Netherlands (six novel mutations). The c.500G>A mutation was found in a Belgian and Turkish family. The Turkish family had a family member with bilateral pheochromocytoma and hemangioblastomas of the central nervous system (case no. 32165). No phenotype described for the Belgian family (case no. 14482). ACMG evidence codes: 'PP2' because they observe a missense variant in a gene where missense variants are a common mechanism of disease, 'PP4' because the patient's phenotypes or family history are highly specific for a disease with single genetic etiology.
PatientID: 121
KindredID: 121
Case: Sex Unknown, 14Y0M, Ethnicity Unknown
DiseaseAssertion: VHL
FamilyInfo: N/A
CasePresentingHPOs: HP:0010797; HP:0009711 (Hemangioblastoma, Retinal capillary hemangioma)
CaseHPOFreeText: CNS hemangioblastoma and retinal hemangioblastoma.
CaseNotHPOs: HP:0006770; HP:0002666; HP:0000107; HP:0001732 (Clear cell renal cell carcinoma, Pheochromocytoma, Renal cyst, Abnormality of the pancreas)
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished:N/A
SupplementalData: Table S1, S2 and S3
Variant: Partial Deletion (11kb)
LegacyVariant: N/A
CaseProblemVariantFreeText: N/A
ClinVarID: N/A
CAID: N/A
gnomAD: N/A
VariantEvidence: N/A
MutationType: deletion
CivicName: Partial deletion of 11kb
MultipleGeneVariants: N/A
c.500G > A
PatientID: None
KindredID: 14
Case: age, sex, ethnicity unknown
DiseaseAssertion: Unknown
FamilyInfo: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: Described as a positive control but not stated anything further
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: Likely previously published - not clear where the controls came from/ how they were used.
SupplementalData: N/A
Variant: p.R167Q (c.500G>A)
CaseProblemVariantFreeText: N/A
LegacyVariant: N/A
ClinVarID: 2216, https://www.ncbi.nlm.nih.gov/clinvar/variation/2216/
CAID: N/A
gnomAD: 0.000003977, https://gnomad.broadinstitute.org/variant/3-10191507-G-A
VariantEvidence: N/A
MutationType: missense_variant; transition
CivicName: R167Q (c.500G>A)
MultipleGeneVariants: N/A
c.250G > T(p.Val84Leu)
74 patients (38 males, 36 females; 24 with prior sequencing data) with pheochromoctyoma were first analyzed by denaturing high performance liquid chromatography (dHPLC). PCR of all exons of VHL was performed on leukocyte DNA extracted from stored blood samples, and those showing variance were sequenced. These patients had presented with clinical features and/or family history suggestive of a germline mutation, leading to their referral for genetic testing. 2 patients found with the V84L (c.250G>T) VHL germline mutation were listed. No family history was mentioned.
Uptake of genetic testing and long-term tumor surveillance in von Hippel-Lindau disease
PMID: 20064270
Gene: VHL
StandardizedReferenceSequence: NM_000551.3
p.F76del
PatientID: None (II)
KindredID: 1
Case: Sex and Ethnicity unknown; Age >18Y0M
DiseaseAssertion: hemangioblastoma
FamilyInfo: Total of 4 family members belonging to Family 1 (see Table 2; or follow KindredID 1)
CasePresentingHPOs: HP:0010797 (hemangioblastoma)
CaseHPOFreeText: 3 HB at first screening, and same by final screening (5 year follow up).
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: 16572651
SupplementalData: N/A
Variant: p.F76del (c.227_229del)
CaseProblemVariantFreeText: N/A
LegacyVariant: N/A
ClinVarID: 223166 https://www.ncbi.nlm.nih.gov/clinvar/variation/223166/
CAID: N/A
gnomAD: N/A
VariantEvidence: N/A
MutationType: inframe_deletion
CivicName: p.F76del
MultipleGeneVariants: N/A
c.593T>C, p.L198P
PatientID: II-1
KindredID: Family C
Case: M, 45Y0M, Ethnicity unknown
DiseaseAssertion: VHL
FamilyInfo: Only this one member was studied. This mutation was said to be a de novo, although no more inforation provided. However the asymptomatic father of patient was also a carrier of the same polymorphism (c.74C>T, p.P25L).
CasePresentingHPOs: HP:0006748; HP:0030405; HP:0009711 (Adrenal pheochromocytoma; pancreatic neuroendocrine tumour; retinal capillary hemangioma)
CaseHPOFreeText: At the age of 15, patient had pancreatic tumor (malignant pancreatic neuroendocrine tumor). At the age of 16, MRI revealed suprarenal tumor masses bilaterally (pheochromocytomas in the adrenal glands), as well as optic nerve hemangioblastomas of the right eye. At the age of 25, he shows no signs of metastases or new VHL-associated tumors, but since the age of 23, he has been suffering from HLAB27-positive ankylosing spondylitis.
CaseNotHPOs: HP:0005584; HP:0010797 (renal cell carcinoma; hemangioblastoma)
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: N/A
Variant: p.L198P (c.593T>C)
LegacyVariant: N/A
CaseProblemVariantFreeText: N/A
ClinVarID: 223235 https://www.ncbi.nlm.nih.gov/clinvar/variation/223235/
gnomAD: N/A
VariantEvidence: N/A
MutationType: missense_variant;transition
CivicName: L198P (c.593T>C) AND P25L (c.74C>T)
MultipleGeneVariants: Germline, VHL, c.74C>T (p.Pro25Leu)
VHLE2c.460C>Tp.P154S
314 Chinese patients with Pheochromocytoma/paraganglioma (PPGL) from Peking Union Medical College Hospital, China, were included in this study for germline profiling. The majority of patients underwent surgery and were histopathologically diagnosed with PPGL. For patients who had an unresectable or metastatic tumor, PPGL diagnosis was determined based on clinical features (headache, palpitations, sweating, etc). Genomic DNA was extracted from peripheral blood of all 314 PPGL patients, and detect potential variants in 12 known genes associated with hereditary PPGL (SDHA, SDHB, SDHC, SDHD, SDHAF2, FH, VHL, RET, NF1, MAX, TMEM127, and KIF1B) using next-generation and Sanger sequencing. Germline variants were detected in 29% of the 314 PPGL patients. Patient #89 is a female PPGL patient who was diagnosed with retroperitoneal paraganglioma at age 39. She was also 39 when metastasis was detected. Germline genetic testing revealed a missense p.P154S(c.460C>T) variant in exon 2 of the VHL gene. Patient 89 does not have family history of PPGL.
P12PCC VHL c.292T>C
PatientID: P12
KindredID: 9
Case: Sex Unknown, Age Unknown, Ethnicity Unknown
DiseaseAssertion: pheochromocytoma
FamilyInfo: N/A
CasePresentingHPOs: HP:0002666 (pheochromocytoma)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: N/A
Variant: p.Y98H (c.292T>C)
LegacyVariant: N/A
CaseProblemVariantFreeText: N/A
ClinVar: 2223 https://www.ncbi.nlm.nih.gov/clinvar/variation/2223/
CAID: N/A
gnomAD: 0.00001343 https://gnomad.broadinstitute.org/variant/3-10183823-T-C
VariantEvidence: N/A
MutationType: missense_variant;transition
CivicName: Y98H (c.292T>C)
MultipleGeneVariants: N/A
c.500G>A p.Arg167Gln
PatientID: VHL 9
KindredID: VHL 9
Case: Sex, Age, Ethnicity unknown
DiseaseAssertion: hemangioblastoma
FamilyInfo: N/A
CasePresentingHPOs: HP:0010797 (hemangioblastoma)
CaseHPOFreeText: Two samples of VHL hemangioblastomas were represented here (.1, .2)
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: N/A - although likely duplicated in 24132471
SupplementalData: Yes - See Supplementary Table 1
Variant: p.R167Q (c.500G>A)
LegacyVariant: N/A
CaseProblemVariantFreeText: N/A
ClinVarID: 2216 https://www.ncbi.nlm.nih.gov/clinvar/variation/2216/
CAID: N/A
gnomAD: 0.000003977 https://gnomad.broadinstitute.org/variant/3-10191507-G-A
VariantEvidence: N/A
MutationType: missense_variant;transition
CivicName: R167Q (c.500G>A)
MultipleGeneVariants: Somatic, VHL, c.292C>A p.Tyr98*
Molecular analysis of germline DNA confirmed a disease-causing mutation in the VHL gene (c.4641G > A).
ArticleReferenceSequence: Not specified – Assumption: variants assumed to have been documented by the author under reference sequence NM_000551.3
GenotypingMethod: Molecular analysis of germline DNA
SamplingMethod: N/A
A 51‐year‐old Spanish man was followed up in cardiology for preexcitation in Wolff–Parkinson–White syndrome since the age of 18, with an electrocardiogram demonstrating a short PR interval, a positive delta wave in diaphragmatic and lateral side, negative in V1, and positive in V2‐V6.
Case#: 51-year-old Spanish man
DiseaseAssertion: Hypertrophic cardiomyopathy
FamilyInfo: Familial HCM
ParentalTesting:
CasePresentingHPOs: Hypertrophic cardiomyopathy
CaseHPOFreeText: not reported
CaseNotHPOs: not reported
CaseNotHPOFreeText: not reported
CasePreviousTesting: not reported
Genotyping Method: Genetic testing/sequencing
FunctionalAnalysis:
Variant: g.47363647G>A, p.Ala562Val
ClinVar: not found
CAID: CA078267
gnomAD: not found
AdditionalInfo: not reported
Familial hypertrophic cardiomyopathy associated with a new mutation in gene MYBPC3
PMID: 28265379
Gene: MYBPC3
HGNC ID: 7551
Novel frameshift variant in MYL2 reveals molecular differences between dominant and recessive forms of hypertrophic cardiomyopathy
PMID: 32453731
Gene: MYL2
HGNC ID: 7583
proband with infantile hypertrophic cardiomyopathy
Case1: Male, Infant, Tunisian
DiseaseAssertion: infantile-onset HCM and mitral valve dysplasia
FamilyInfo: Family with consanguinity in which four children had died before one year of age. The father (37 years old) and mother (27 years old) of the proband are consanguineously related. Two infants (VI:1 and VI:2) died at less than 30 days of age from cardiorespiratory arrest, and two (VI:3 and VI:4, proband) of them displayed abnormal cardiac findings on chest roentgenogram. While all four children displayed hepatomegaly and general hypotonia, VI:3 and VI:4 had a marked increase in heart size and died from refractory cardiogenic shock. The status of the MYL2 allele in siblings is unknown. The proband (fs/fs) was homozygous for the MYL2-fs allele while the parents were found to be heterozygous (fs/wt) carriers. The father (37 years old) and mother (27 years old) of the proband are consanguineously related, were asymptomatic from a cardiac standpoint and had normal cardiac anatomy and function as evaluated by an echocardiogram
ParentalTesting: Homozygous variant in the proband and that the parents are heterozygous carriers using Sanger DNA sequencing of the genomic region. Father (37 years old) and mother (27 years old) were asymptomatic from a cardiac standpoint and had normal cardiac anatomy and function as evaluated by an echocardiogram
CasePresentingHPOs: HP:0200128, HP:0001653, HP:0002092, HP:0001639, HP:0002240
CaseHPOFreeText: Showed a rapid decline in health and was treated for various periods in neonatal intensive care units. The patient also displayed severe mitral valve regurgitation with abnormal thickening of the mitral valve leaflets and pulmonary arterial hypertension. Post-mortem examination of the proband’s heart confirmed severe biatrial dilatation, significant biventricular hypertrophy with small ventricular cavities and severe mitral valve dysplasia
CaseNotHPOs: NR
CaseNotHPOFreeText: no gross developmental defects
CasePreviousTesting: No prior genetic testing reported before exome sequencing
Genotyping Method: Performed exome sequencing on the proband. Exome libraries were constructed using the Agilent SureSelectQXT Target Enrichment System for Illumina Multiplexed Sequencing Protocol (Agilent Technologies, CA). DNA libraries were captured with the Agilent Clinical Research Exome Kit. Paired-end 150 base pair reads were generated for exome-enriched libraries sequenced on the Illumina HiSeq 4000 to a targeted depth of 100× coverage
FunctionalAnalysis: Functional analysis performed. Immunohistochemical analysis of MYL2 expression in the proband’s ventricular myocardium shows a remarkable reduction in the expression of MYL2 as compared to control. Also, MYL2 mRNA was detected in the ventricle of the proband by RT-PCR. This suggests that the frameshift variant adversely affects the levels of MYL2 protein in the proband. Using immunoblot analysis, we observed that overexpression of the MYL2-fs variant was significantly reduced compared to stop-gain variants and the missense variant. When the H9c2 cells were treated with MG-132 after transfection with the MYL2-fs construct, the GFP signal corresponding to MYL2-fs was recovered. The in vitro experiments indicate that the MYL2-fs variant is not stable and that proteasome-mediated degradation of the translated product plays a key role in the instability of the protein. The overexpression of the fs variant identified in our proband or the MYL2-G162R missense variant failed to rescue the phenotype. Results reported in Figures 2, 3, and 4.
Variant: NM_000432.3:c.431_432delCT
ClinVar: NR
CAID: UnregisteredVariant
gnomAD: NR
AdditionalInfo: 4 siblings who died before 1 year of age but MYL2 genotyping was only confirmed in the proband (VI:4)
5.5-months-old child
Case#: Deceased child, female; age 5.5 months
DiseaseAssertion: Hypertrophic cardiomyopathy with endomyocardial fibroelastosis
FamilyInfo: The mother carried c.2373dup, and the father carried c.592G>T.
ParentalTesting: The mother carried c.2373dup, and the father carried c.592G>T.
CasePresentingHPOs: HP:0001706 HP:0200128 HP:0012664 HP:0002094 HP:0000961
CaseHPOFreeText: Acute heart failure; massive biventricular cardiac enlargement; biventricular dysfunction; progressive dyspnea; blue lips; pale appearance; endocardial fibrosis; cardiopulmonary arrest.
CaseNotHPOFreeText: No congenital heart disease or valve abnormalities were found at autopsy
Genotyping Method: Postmortem molecular testing
Variant: MYBPC3 c.592G>T (p.Asp198Tyr); missense
MYBPC3 c.2373dup, p.Trp792Valfs*41); frameshift duplication
ClinVar: c.592G>T: NR; c.2373dup: 42619
CAID: c.592G>T: NR; c.2373dup: CA012139
gnomAD: c.592G>T was not observed in more than 123,000 individuals; c.2373dup: 0.0017% overall
AdditionalInfo: The child died from severe early-onset cardiac disease at 5.5 months. Autopsy showed endomyocardial fibroelastosis and severe biventricular involvement.
Identification of a novel missense mutation in the TPM1 gene via exome sequencing in a Chinese family with dilated cardiomyopathy
PMID: 35029218
Gene: TPM1
HGNC ID: 12010
The proband (II-1) was a 40-year-old Chinese Han male born at full term after an uncomplicated pregnancy and delivery.
Case#: Proband(II-1)
DiseaseAssertion: DCM1Y
FamilyInfo: Chinese Han family with DCM phenotypes.
ParentalTesting: not reported
CasePresentingHPOs: HP:0001644
CaseHPOFreeText: Proband diagnosed with dilated cardiomyopathy and found to carry a TPM1 variant.
CaseNotHPOs: not reported
CaseNotHPOFreeText: not reported
CasePreviousTesting: not reported
Genotyping Method: Next-generation sequencing (NGS), confirmed by Sanger sequencing
FunctionalAnalysis: none reported
Variant: TPM1 c.340G>C (p.E114Q) missense variant
ClinVar: not found
CAID: CA392721071
gnomAD:
AdditionalInfo:
The second daughter (IV‐5) is the index case
Case1: 14 month, female
DiseaseAssertion: dilated cardiomyopathy
FamilyInfo:The three siblings' cases were born to consanguineous parents. They had DCM and died from decompensated heart failure around the age of 12 months
ParentalTesting: Sanger Sequencing determined the parents carried the variant at the heterozygous state (Figure 1)
CasePresentingHPOs: HP:0002094, HP:0002099, HP:0002098, HP:0002090,
CaseHPOFreeText:productive cough, and whining, wheezing, mitral and tricuspid regurgitation
CaseNotHPOs: NR
CaseNotHPOFreeText:no sign of ischemia,
CasePreviousTesting: cardiac ultrasound
Genotyping Method: sanger sequencing
FunctionalAnalysis: NR
Variant: TNNI3 (NM_000363.5): c.204delG;p.(Arg69AlafsTer8)
ClinVar: 179447
gnomAD: not found
Homozygous TNNI3 frameshift variant in a consanguineous family with lethal infantile dilated cardiomyopathy
Case IV.2 is an 8-year-old male from family B (Fig. 1b), who was diagnosed with DCM at the age of 6. He underwent heart transplantation soon after diagnosis. The only other clinical feature noted was horseshoe kidney. The affected brother (IV.1) died at the age of 2 of SCD and renal failure.
Case#: Family B, Case IV.2; 8-year-old male; diagnosed at age 6
DiseaseAssertion: Dilated cardiomyopathy (DCM)
FamilyInfo: Positive family history of sudden cardiac death (SCD). The proband's brother (IV.1) died at age 2 of SCD and renal failure. Both parents (III.1 and III.2) were asymptomatic heterozygous carriers of MYL3 c.106G>T. Two unaffected siblings were tested: IV.3 was wild-type and IV.4 was heterozygous (Fig. 1b; Supplementary Fig. S2b).
ParentalTesting: Both parents (III.1 and III.2) were confirmed heterozygous carriers of MYL3 c.106G>T by PCR and bidirectional Sanger sequencing, supporting autosomal recessive inheritance (Supplementary Genetic Findings; Fig. S2b).
CasePresentingHPOs: HP:0001644 (Dilated cardiomyopathy); HP:0000085 (Horseshoe kidney); HP:0005162 (Reduced left ventricular ejection fraction).
CaseHPOFreeText: DCM diagnosed at age 6; heart transplantation performed shortly after diagnosis. Clinical evaluation revealed horseshoe kidney, severe left ventricular dysfunction (LVEF 15–20%), moderate right ventricular dysfunction (TAPSE 9 mm), chamber cardiomegaly on coronary CT angiography, and rapid ventricular tachycardia on ECG (Main text, Family B; Supplementary Results, p. 6).
CaseNotHPOs: NR
CaseNotHPOFreeText: NR
CasePreviousTesting: NR (no prior diagnostic genetic testing reported before the study's exome sequencing)
Genotyping Method: Exome sequencing identified the homozygous MYL3 c.106G>T (p.Glu36Ter) variant in the proband (IV.2). PCR and bidirectional Sanger sequencing validated the variant and confirmed segregation in the parents and two unaffected siblings (Supplementary Methods; Supplementary Genetic Findings; Fig. S2b).
FunctionalAnalysis: Zebrafish cmlc1 knockdown and rescue experiments were performed using human MYL3 RNA containing c.106G>T (p.Glu36Ter). Unlike wild-type MYL3 RNA, the mutant RNA failed to rescue the cardiac phenotype, with persistent cardiac edema, ventricular dysfunction, and atrial dilation (Fig. 2; Supplementary Methods; Supplementary Movie S7).
Variant: MYL3 NM_000258.2:c.106G>T (p. Glu36Ter); homozygous nonsense variant
ClinVar: NR
CAID: CA352499542
gnomAD: NR
AdditionalInfo: The authors classified the homozygous MYL3 c.106G>T (p.Glu36Ter) nonsense variant as pathogenic. The variant introduces a premature termination codon at amino acid 36. The proband was born to asymptomatic, consanguineous (first-cousin) parents of Bakhtiyari ancestry. Family segregation and zebrafish functional studies provide supporting evidence (Supplementary Results; Supplementary Genetic Findings; Supplementary Table S2).
Case VI.1, from family C, was a female of apparently healthy second cousin parents. She was diagnosed with unclassified cardiomyopathy at the age of 2.5 years and died at the age of 8 years of SCD. Family history was positive for cardiac disease and occurrence of SCD in three family members (V.5, V.6, and V.8), who had been diagnosed with unclassified cardiomyopathy between the ages of 2 and 3 and had died between 5 and 9 years of age (Fig. 1c). There was no record of cardiac evaluation available for these individuals. The 40-year-old mother (V.2) was offered genetic testing following the death of her daughter (VI.1). Unfortunately, there was no tissue available from the deceased individual VI.1.
Case#: Family C, Case VI.1; female; diagnosed at age 2.5 years; died at age 8
DiseaseAssertion: Unclassified cardiomyopathy
FamilyInfo: Family C has a positive family history of childhood-onset cardiomyopathy and sudden cardiac death. The affected individual (VI.1) was diagnosed with cardiomyopathy at age 2.5 years and died at age 8. Three maternal relatives (V.5, V.6, and V.8) are depicted as affected and deceased in the pedigree (Fig. 1C). Both parents (V.1 and V.2) were clinically unaffected heterozygous carriers of the MYL3 c.482-1G>A splice-acceptor variant. The genotype of VI.1 could not be confirmed because DNA was unavailable.
ParentalTesting: PCR and bidirectional Sanger sequencing confirmed that both parents (V.1 and V.2) were heterozygous carriers of MYL3 c.482-1G>A. Direct testing of the affected daughter (VI.1) was not possible because DNA was unavailable. Her homozygous genotype was therefore suspected but not confirmed (Fig. 1C; Supplementary Genetic Findings).
CasePresentingHPOs: HP:0001638 (Cardiomyopathy); HP:0001645 (Sudden cardiac death).
CaseHPOFreeText: Female diagnosed with unclassified cardiomyopathy at age 2.5 years; died of sudden cardiac death at age 8 (Family C, Fig. 1C).
CaseNotHPOs: NR (no patient-specific negative HPO findings confirmed for VI.1).
CaseNotHPOFreeText: The authors reported no evidence of muscle weakness by neurological examination or history among affected individuals from the three families; however, it is unclear whether this assessment specifically included VI.1.
CasePreviousTesting: NR (no prior genetic testing reported for VI.1).
Genotyping Method: Genetic analysis of the affected individual's mother (V.2) identified MYL3 c.482-1G>A. PCR and bidirectional Sanger sequencing validated the variant and confirmed both parents (V.1 and V.2) as heterozygous carriers. VI.1 was not directly genotyped because DNA was unavailable (Supplementary Genetic Findings; Fig. 1C and S2C).
FunctionalAnalysis: A minigene splicing assay in human HEK293FT cells demonstrated that MYL3 c.482-1G>A causes abnormal RNA splicing. The predominant outcome (~75%) was skipping of the 78-bp exon 5, producing an in-frame deletion (p.Gly161_Glu186del). A less frequent outcome (~25%) was deletion of the first nucleotide of exon 5, causing a frameshift (p.Gly161Valfs*4). Both outcomes are predicted to disrupt EF-hand domains. The authors note that the minigene assay may not fully reflect in vivo splicing frequencies (Supplementary Results, pp. 7–8; Fig. 2E–I).
Variant: MYL3 c.482-1G>A (rs727503300)
ClinVar: 164486
CAID: CA013932
gnomAD: NR MYL3 c.482-1G>A was not found in the gnomAD v4 (GRCh38) region results at chr3:46,860,813. Allele frequency not reported for this variant in the searched dataset.
AdditionalInfo: The affected individual (VI.1) died at age 8, and DNA was unavailable for direct genetic testing. Both clinically unaffected parents (V.1 and V.2) were confirmed heterozygous carriers of MYL3 c.482-1G>A, suggesting that VI.1 may have inherited the variant from both parents; however, her genotype remains unconfirmed. A minigene assay demonstrated that the variant disrupts RNA splicing, predominantly causing exon 5 skipping, with a less frequent frameshift-producing splicing event. These functional findings support a damaging effect of the variant but do not establish VI.1's genotype (Fig. 1C; Fig. 2E–I; Supplementary Genetic Findings and Minigene Assay Results).
Case III.7, a 38-year-old female from family A, was diagnosed with HCM at the age of 26 following dyspnea. Family history was positive for HCM and occurrence of SCD in four family members (Fig. 1a).
Case#: Family A, Case III.7; 38-year-old female; diagnosed at age 26
DiseaseAssertion: Hypertrophic cardiomyopathy (HCM)
FamilyInfo: Positive family history of HCM and SCD. Mother (II.4), brother (III.8), uncle (II.7), and cousin (III.11) died of SCD at ages 55, 26, 57, and 24, respectively. The proband's three children (IV.3, IV.4, IV.5) were homozygous for the MYL3 variant but had normal echocardiograms at ages 18, 13, and 6.
ParentalTesting: Supplementary Table S2 reports parental testing supportive of PM3 (variants in trans). However, DNA was unavailable for the proband's deceased mother (II.4), and individual parental genotypes were not specified in the supplementary genetic findings.
CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy); HP:0002094 (Dyspnea); HP:0001653 (Mitral regurgitation); HP:0001712 (Left ventricular hypertrophy)
CaseHPOFreeText: HCM diagnosed at age 26 following dyspnea. At age 38, echocardiography showed reverse-curvature HCM with asymmetric left ventricular hypertrophy involving anterior, anterolateral, and lateral segments; maximum wall thickness 22 mm; severe mitral regurgitation; LVEF 55%; E/e' ratio 16.4; resting LVOT gradient 9 and post-maneuver gradient 30. Holter monitoring showed no arrhythmias (Supplementary Results, pp. 5–6; Table S1; Fig. S1).
CaseNotHPOs: HP:0001324 (Muscle weakness)
CaseNotHPOFreeText: Neurological evaluation revealed normal muscle tone, strength 5/5 in upper and lower limbs, no distal or proximal muscle atrophy or fasciculations, and normal creatine phosphokinase levels.
CasePreviousTesting: Exome sequencing was performed; no rare, likely pathogenic variants in other cardiomyopathy-associated genes identified after filtering.
Genotyping Method: Exome sequencing identified the MYL3 variant; bidirectional Sanger sequencing validated the variant. Familial genotyping supported recessive inheritance (Fig. 1a).
FunctionalAnalysis: Zebrafish cmlc1 knockdown and rescue experiments were performed using human MYL3 RNA carrying c.170C>A (p.Ala57Asp). Mutant RNA showed partial phenotypic rescue but no statistically significant improvement in ventricular contractility compared with knockdown alone (Fig. 2a-d).
Variant: MYL3 NM_000258.2:c.170C>A (p.Ala57Asp); homozygous missense variant; rs139794067
ClinVar: 43121
CAID: CA013575
gnomAD: Allele frequency 0.000163 (0 homozygotes), as reported in Supplementary Table S2.
AdditionalInfo: Family A, Case III.7. Clinical characteristics and genetic findings described in the Results section (Fig. 1a and 1d-e). Functional experiments described in Fig. 2. The authors classified c.170C>A as a variant of uncertain significance (VUS).
Autosomal recessive cardiomyopathy and sudden cardiac death associated with variants in MYL3
PMID: 33288880
Gene: MYL3
HGNC ID: 7584
The proband
Case#: Female, Hispanic, 4
DiseaseAssertion:Dilated cardiomyopathy
FamilyInfo: Uncle who died at a young age of sudden cardiac death.
ParentalTesting:
CasePresentingHPOs: HP:0001638
"severe decompensated cardiomyopathy at age 4."
CaseHPOFreeText: NR
CaseNotHPOs: NR
CaseNotHPOFreeText:NR
CasePreviousTesting: NR
Genotyping Method: commercial genetic testing and Sanger sequencing
FunctionalAnalysis:
Variant: NM_001276345.2:c.*187C>T
ClinVar: NR
CAID:CA2649785730
gnomAD:NR
AdditionalInfo:
PMID: 26498512
Gene: TNNT2
HGNC ID: 11949
(IV-2)
Case#: IV-2; female; age 51; Chinese family
DiseaseAssertion: Hypertrophic cardiomyopathy
FamilyInfo: IV-2 is the mother of V-1
CasePresentingHPOs: HP:0001712 HP:0005144
CaseHPOFreeText: Atypical hypertrophy with a septal thickness of 23 mm; exertional angina for 10 years.
Genotyping Method: Sanger sequencing and targeted next-generation sequencing
Variant: c.3624delC, frameshift
ClinVar: 42727
CAID: CA014493
AdditionalInfo: Also carried CACNB2 p.Ser533Leu and DSP p.Arg1308Gln.
patient (V-1)
Case#: V-1; male; age 28; Chinese family
DiseaseAssertion: Hypertrophic cardiomyopathy
FamilyInfo: V-1 is part of a large consanguineous HCM pedigree. Family segregation information was reported for the MYBPC3 variant. V-1 died suddenly at age 29
CasePresentingHPOs: HP:0001712 HP:0005144 HP:0032092
CaseHPOFreeText: Left ventricular hypertrophy; increased interventricular septal thickness; left ventricular outflow tract obstruction
Genotyping Method: Sanger sequencing and next-generation sequencing
Variant: c.3624delC, missense
ClinVar: 42727
CAID: CA014493
(IV-6)
Case#: IV-6; female; age 64; Chinese family
DiseaseAssertion: Hypertrophic cardiomyopathy
FamilyInfo: IV-6 is a member of the MYBPC3-positive HCM pedigree
CasePresentingHPOs: HP:0001712 HP:0005144
CaseHPOFreeText: Moderately affected, asymmetrical hypertrophy with a maximum wall thickness of 15 mm; normal left ventricular dimensions and systolic function.
CaseNotHPOFreeText: No cardiac symptoms or cardiac events were reported.
Genotyping Method: Sanger sequencing and targeted next-generation sequencing
Variant: c.3624delC, frameshift
ClinVar: 42727
CAID: CA014493
AdditionalInfo: No additional CACNB2 variant was reported.
6
Case#: Family #6; 36-year-old male
DiseaseAssertion: Arrhythmogenic right ventricular cardiomyopathy (ARVC); diagnosed according to the 2010 revised Task Force Criteria
FamilyInfo: Family #6. No informative segregation evidence specifically linking the MYL3 variant to ARVC was reported. The authors noted that family screening was incomplete or normal in other families, but did not specify which circumstance applied to Family #6.
ParentalTesting: NR
CasePresentingHPOs: HP:0006682 (PVCs)
CaseHPOFreeText: Symptomatic presentation; major right ventricular structural abnormality; minor ECG repolarization criterion; 1,181 ventricular ectopic beats on Holter monitoring; sustained ventricular arrhythmia (specific rhythm not reported).
CaseNotHPOs: HP:0001279 (Syncope); HP:0005162 (Abnormal left ventricular function)
CaseNotHPOFreeText: No cardiac syncope or left ventricular dysfunction reported. Absence of cardiac syncope does not necessarily exclude every form of syncope.
CasePreviousTesting: No pathogenic or likely pathogenic variants identified in established ARVC-associated genes (PKP2, DSG2, DSP, DSC2, JUP, TMEM43, PLN, SCN5A). Subsequent screening included nine sarcomere genes: ACTC1, MYBPC3, MYH7, MYL2, MYL3, TNNC1, TNNI3, TNNT2, and TPM1. The study used broad genetic testing, including whole-exome sequencing in a subset of probands; whether Family #6 underwent whole-exome sequencing was not specified.
Genotyping Method: Sarcomere-gene sequencing and deletion/duplication analysis through clinical cardiomyopathy panels, research-based next-generation sequencing panels, or whole-exome sequencing. The exact initial platform for Family #6 was not specified. Identified variants were confirmed by PCR amplification and Sanger sequencing.
FunctionalAnalysis: NR
Variant: MYL3 NM_000258.2:c.461G>A (p.Arg154His); missense variant; exon 4
ClinVar: 14062
CAID: CA013861
gnomAD: MYL3 c.461G>A (p.Arg154His), GRCh38: 3-46859495-C-T. gnomAD v4: Exome AF = 0.00003557; Genome AF = 0.00001971; Total AF = 0.00003408. European (non-Finnish): AC = 52, AF = 0.00004407. https://gnomad.broadinstitute.org/variant/3-46859495-C-T?dataset=gnomad_r4
AdditionalInfo: Murray et al. (2018), Tables 1 and 2, Family #6. The MYL3 variant was classified as likely pathogenic (LP) according to ACMG criteria, with a PolyPhen-2 score of 0.861. The proband met criteria for definite ARVC, with no reported left ventricular dysfunction. Although the variant was rare and computationally predicted to be damaging, the authors emphasized that evidence demonstrating a causal relationship between sarcomere variants and ARVC remained insufficient. No direct functional analysis of this variant was performed in the study.
Identification of sarcomeric variants in probands with a clinical diagnosis of arrhythmogenic right ventricular cardiomyopathy (ARVC)
PMID: 29709087
Gene: MYL3
HGNC ID: 7584
Myosin-binding Protein C Compound Heterozygous Variant Effect on the Phenotypic Expression of Hypertrophic Cardiomyopathy
PMID: 28538763
Gene: TNNT2
HGNC ID: 11949
The proband
Case#: Male, 17
DiseaseAssertion: hypertrophic cardiomyopathy
FamilyInfo: All family members were asymptomatic, with normal TTE and ECG, with no evidence of VH.
ParentalTesting:
CasePresentingHPOs: HP:0001639, HP:0001279, HP:0001670, HP:0032092, HP:0031295
CaseHPOFreeText: diastolic type II dysfunction,
CaseNotHPOs: NR
CaseNotHPOFreeText: NR
CasePreviousTesting: genetic analysis of the proband was performed through direct sequencing of the three sarcomere genes: MYH7, MYBPC3 and TNNT2
Genotyping Method: Sanger Sequencing
FunctionalAnalysis: NR
Variant: NR
ClinVar:NR
CAID: NR
gnomAD: NR
AdditionalInfo: underwent clinical and cardiovascular examination, including a 12-lead electrocardiogram (ECG), transthoracic echocardiography (TTE) and 24-hour Holter monitoring. TNNT2 sequenced, but not reported.
A young girl, 11 years old, died suddenly without any specific trigger factor during her usual daily activities.
Case#: 11 year old girl
DiseaseAssertion: hypertrophic cardiomyopathy
FamilyInfo: unremarkable
ParentalTesting: Both parents were tested and neither carried the variant
CasePresentingHPOs: HP:0001639 HP:0011675
CaseHPOFreeText: Post-mortem examination revealed asymmetric non-obstructive hypertrophy of the interventricular septum.
CaseNotHPOs: Syncope absent
CaseNotHPOFreeText: No complaints, normal exercise tolerance, no syncope, no medications, and no significant family history.
CasePreviousTesting: Autopsy and sudden cardiac death investigation.
Genotyping Method: Genetic testing performed as part of post-mortem investigation; familial cascade screening.
FunctionalAnalysis:
Variant: TPM1 c.656A>T (p.Asp219Val, p.D219V)
ClinVar: absent
CAID: CA2998480361
gnomAD: absent
AdditionalInfo: Variant classified as likely pathogenic (Class IV) by the authors and determined to be de novo.
De Novo Asp219Val Mutation in Cardiac Tropomyosin Associated with Hypertrophic Cardiomyopathy
PMID: 36613463
Gene: TPM1
HGNC ID: 12010
The index patient
Case#: Female, 4 months, Swedish
DiseaseAssertion: dilated cardiomyopathy
FamilyInfo: Strong family history of DCM and faily history of SCD due to DCM. Maternal grandfather had enlarged left ventricle.
ParentalTesting:
CasePresentingHPOs: HP:0005162, HP:0031295, HP:0001653,
CaseHPOFreeText: enlarged left ventricle,
CaseNotHPOs:HP:0011947
CaseNotHPOFreeText: circulatory collapse
CasePreviousTesting: NR
Genotyping Method: Sanger sequencing
FunctionalAnalysis: NR
Variant: NM_001276345.2:c.548G>A
ClinVar:43649
CAID: CA004727
gnomAD:NR
AdditionalInfo: During cardiac catheterization, cardiac resuscitation due to circulatory collapse was needed.
Novel Genetic Variants in BAG3 and TNNT2 in a Swedish Family with a History of Dilated Cardiomyopathy and Sudden Cardiac Death
PMID: 28669108
Gene: TNNT2
HGNC ID: 11949
healthy 46 years old active, athletic, healthy individual
Case1:Male, 46 years old
DiseaseAssertion:
FamilyInfo: 3 generations of asymptomatic carriers
ParentalTesting:
CasePresentingHPOs:
CaseHPOFreeText:
CaseNotHPOs:HP:0001712
CaseNotHPOFreeText:Left Ventricular hypertrophy
CasePreviousTesting:
Genotyping Method: Not Stated
FunctionalAnalysis:
Variant: c.170C>A VUS
ClinVar:43121
CAID:CA013575
gnomAD:
AdditionalInfo:
Determining the Pathogenicity of a Genomic Variant of Uncertain Significance Using CRISPR/Cas9 and Human Induced Pluripotent Stem Cells
PMID: 29914921
Gene: MYL3
HGNC ID: 7584
Application of Long-Read Nanopore Sequencing to the Search for Mutations in Hypertrophic Cardiomyopathy
PMID: 36555486
Gene: MYBPC3
HGNC ID: HGNC:7551
Combinatorial interactions of genetic variants in human cardiomyopathy
PMID: 30923642
Gene: TPM1
HGNC ID: 12010
he proband initially presented with severe heart failure and required heart transplantation at age 14
Case#: Patient A
DiseaseAssertion: Dilated Cardiomyopathy (DCM)
FamilyInfo: Large multigenerational family with DCM. Six family members identified. TPM1 and VCL variants are connected to disease.
ParentalTesting: Both parents presented with DCM and TPM1 variant c.97G>A.[p.glu33Lys, p.E33K].
CasePresentingHPOs: HP:0001644 HP:0012664 HP:0001635
CaseHPOFreeText: severe heart failure and required heart transplant. Left ventricular ejection fraction.
CaseNotHPOs:unkown
CaseNotHPOFreeText: unkown
CasePreviousTesting: unkown
Genotyping Method: PCR amplification & Sanger sequencing.
FunctionalAnalysis: functional data support that TPM1 and VCL variants act synergistically to impact cardiomyocyte contractility and sarcomeric organization and suggest that together these variants may perturb sarcomeric–costameric interactions.
Variant: TPM1 c.97G>A (p.Glu33Lys; E33K)
ClinVar: not found
CAID: CA018447
gnomAD: not reported
AdditionalInfo:
Patient-specific induced pluripotent stem cell properties implicate Ca2+-homeostasis in clinical arrhythmia associated with combined heterozygous RYR2 and SCN10A variants
PMID: 37122207
Gene: TNNT2
HGNC ID: 11949
The proband, a four-month-old boy, presented with polymorphic ventricular tachycardia.
Case#: 4 month old boy
DiseaseAssertion: Polymorphic ventricular tachycardia
FamilyInfo: His father carried the RYR2 variant and had ventricular premature beats. His mother carried the SCN10A variant and was asymptomatic.
ParentalTesting: Yes. Familial genetic testing showed the RYR2-A1855D variant was inherited from the father and the SCN10A-Q1362H variant was inherited from the mother.
CasePresentingHPOs: HP:0004756
CaseHPOFreeText: 4-month-old male presenting with polymorphic ventricular tachycardia.
CaseNotHPOs: not reported
CaseNotHPOFreeText: not reported
CasePreviousTesting: Clinical cardiac evaluation followed by genetic testing
Genotyping Method: Genetic testing identified novel heterozygous RYR2-A1855D and SCN10A-Q1362H variants.
FunctionalAnalysis: Functional studies showed abnormal calcium handling, prolonged action potentials, increased susceptibility to early afterdepolarizations, and disrupted Ca2+ homeostasis in cells carrying both variants.
Variant: RYR2 (heterozygous) SCN10A
ClinVar: not found
CAID: not found
gnomAD: not found
AdditionalInfo:
Challenging of ECMO application in pediatric restrictive cardiomyopathy: case report of a novel TNNI3 variant
eight-year-old female
Case1:eight-year-old female
DiseaseAssertion: Restrictive cardiomyopathy (RCM)
FamilyInfo: The patient's parents denied any positive family history of cardiac attacks, cardiovascular issues, hypertension, or coronary artery diseases. There was also no reported history of diabetes or obesity among family members. No inherited diseases, including cardiomyopathies or metabolic disorders, were identified in the family history
ParentalTesting: NR
CasePresentingHPOs:HP:0012378, HP:0001695, HP:0100539, HP:0031352, HP:0034030
CaseHPOFreeText:bilateral pedal edema, shortness of breath after engaging in physical activity, typically lasting for 15 min, enlarged bilateral atrium, segmental thickening of the interventricular septum, segmentally diffuse reduction and lack of coordination in ventricular wall pulse amplitude, mild mitral regurgitation, and diminished left ventricular systolic and diastolic function identified by increased parameters of early diastolic velocity (E wave) and low late filling velocity (A wave) (Figure 1A) abnormal bilateral atrial signals, premature atrial beats, junctional ectopic beats, first-degree atrioventricular block, complete right bundle branch block, prolonged QT interval, and abnormal Q wave (Figure 1B).
CaseNotHPOs: NR
CaseNotHPOFreeText: NR
CasePreviousTesting: echocardiography, genetic screening, imaging assessments, blood gas analysis, blood cell counts, carbon dioxide retention
Genotyping Method: whole-exome sequencing (WES)
FunctionalAnalysis: computational analysis
Variant:TNNI3 c.509G>A p.R170Q
ClinVar:165516
gnomAD: not found
The patient showed some degree of growth retardation at the age of four
Case1: 6 year old, female
DiseaseAssertion: Restrictive cardiomyopathy
FamilyInfo:Both parents were heterozygous carriers, supporting an autosomal recessive inheritance pattern, younger brother showed no abnormalities or signs of the same illness
ParentalTesting: Sanger Sequencing
CasePresentingHPOs:HP:0002094, HP:0012378
CaseHPOFreeText: well below normal weight and height range for patients age, preserved systolic function and diastolic dysfunction, revealed preserved left ventricular systolic function with an ejection fraction, impaired diastolic function, enlarged atrium, wall thickening, impaired ventricular filling
CaseNotHPOs: NR
CaseNotHPOFreeText: comprehensive initial workup, including blood tests and urinalysis, revealed no additional abnormalities
CasePreviousTesting: Echocardiogram, blood tests, urinalysis
Genotyping Method: Whole-exome sequencing
FunctionalAnalysis: NR
Variant: TNNI3 c.406 C > T:p.R136
ClinVar: 488853
gnomAD: not found
Exploring the c.406 C > T variant in TNNI3 gene: pathogenic insights into restrictive cardiomyopathy
Case Report: Mutation in TNNI3(c. 544G>A): a novel likely pathogenic mechanism of neonatal dilated cardiomyopathy
22-day-old newborn boy
Case1: 22-day-old newborn boy
**DiseaseAssertion ** neonatal dilated cardiomyopathy
FamilyInfo: no mutation in the parents
ParentalTesting: whole-exome sequencing
CasePresentingHPOs: HP:0002094, HP:0002789, HP:0010741, HP:0001644, HP:0001640, HP:0002202, HP:0000961, HP:0001259
CaseHPOFreeText: weaning difficulties during hospitalization with intractable low EF heart insufficiency, refractory low ejection fraction, cardiac insufficiency, mild pulmonary hypertension, and mitral and tricuspid insufficiency with mild valve regurgitation, difficulty with ventilator withdrawal, irregular fever, pale face, poor feeding after birth
CaseNotHPOs: NR
CaseNotHPOFreeText: no abnormal symptoms or signs from birth to the 10th day
CasePreviousTesting: Whole-exome sequencing (Figure A), Chest CT, Electrocardiography, Doppler echocardiography (Figures 1A,B), arterial blood gas, routine blood examination, liver function, renal function, serum electrolytes, bacterial endotoxin, G-test, blood culture, sputum culture, and stool tests
Genotyping Method: whole-exome sequencing (WES)
FunctionalAnalysis: NR
Variant: homozygous mutation in 554 based on the 7th exon of the TNNI3 gene (chromosomal position CHR 19:55665403, reference genome HG19): c.544G>A(p.Glu182Lys) (Figure 2A)
ClinVar: not found
CAID: CA021848
gnomAD: not reported
Case Report: Restrictive cardiomyopathy due to a rare mutation in troponin I gene (TNNI3) in a patient
2-year-2-month-old boy located in Yunnan Province, China
Case#: 2 year old, male, from Yunnan Province, China
DiseaseAssertion: Restrictive cardiomyopathy
FamilyInfo:no family history of sudden cardiac death or cardiomyopathy
ParentalTesting: Sanger Sequencing
CasePresentingHPOs:HP:0034031, HP:0001635, HP:0002240,
CaseHPOFreeText:a little puffiness of the eyelids, jugular veins were full but not inflamed, atypical heart beat, edema of the lower limbs, bi-atrial enlargement, left ventricular ejection fraction of 64.6%, normal septal and ventricular wall thickness, trace pericardial effusion atrial and ventricular septum had uneven signals in the localized areas on perfusion imaging under resting state, and gadolinium-delayed enhancement showed a suspicious stripe enhancement of the septum, (Figures 1-3)
CaseNotHPOs:OMIM:145500, HP:0000819, HP:0001698,
CaseNotHPOFreeText: no history of connective tissue disease or radiation therapy, no endocardial thickening
CasePreviousTesting: electrocardiogram, cardiac magnetic resonance,
Genotyping Method: Whole-exome sequencing, sanger sequencing
FunctionalAnalysis: NR
Variant:heterozygous (c.574C > T, p.Arg192Cys) TNNI3
ClinVar: 165510
gnomAD: not found
68-year-old male patient with HCM
Case#: V-1; male; age 68
DiseaseAssertion: Familial hypertrophic cardiomyopathy
FamilyInfo: HCM was reported in the proband’s father and three daughters. The same heterozygous TNNT2 Δ160E variant was identified in all three daughters
CasePresentingHPOs: HP:0001712 HP:0012664 HP:4000141 HP:0004756
CaseHPOFreeText: Left ventricular hypertrophy; progressive left ventricular systolic dysfunction; left ventricular enlargement; cardiomyocyte hypertrophy; sustained ventricular tachycardia; advanced heart failure
CasePreviousTesting: Diagnosed with HCM at age 25; no previous genetic testing reported
Genotyping Method: Ion AmpliSeq cardiovascular research panel screening 404 genes, with direct Sanger sequencing confirmation
FunctionalAnalysis: Patient-derived and isogenic CRISPR/Cas9-edited iPSC-derived cardiomyocytes showed prolonged calcium decay, impaired relaxation, cardiomyocyte hypertrophy, and altered calcium-regulated signaling. EGCG partially improved the calcium and relaxation abnormalities.
Variant: c.478_480del, p.Δ160E; in-frame 3-bp deletion
ClinVar: 43648
CAID: CA004651
Human-Induced Pluripotent Stem Cell–Derived Cardiomyocyte Model for TNNT2 Δ160E-Induced Cardiomyopathy
PMID: 35861968
Gene: TNNT2
HGNC ID: HGNC:11949
Setting up Multiplex Panels for Genetic Testing of Familial Hypertrophic Cardiomyopathy Based on Linkage Analysis
PMID: 27141495
Gene: TNNT2
HGNC ID: 11949
A myosin activator improves actin assembly and sarcomere function of human-induced pluripotent stem cell-derived cardiomyocytes with a troponin T point mutation
PMID: 27199119
Gene: TNNT2
HGNC ID: 11949
Is genomic screening necessary for fetuses who suffer moderate to severe tricuspid regurgitation?
PMID: 31770195
Gene: TNNT2
HGNC ID: 11949
The baby was born
Case#: Female, 6 months
DiseaseAssertion: Dilated cardiomyopathy
FamilyInfo: Mother was age 40 at time of birth, which is a high-risk factor for birth defects
ParentalTesting:
CasePresentingHPOs: HP:0031664, HP:0010438, HP:0005162
CaseHPOFreeText: blood pressure of the four limbs was "92/44 mmHg at the right upper limb, 96/58 mmHg at the left upper limb, 101/60 mmHg at the right lower limb, and 103/54 mmHg at the left lower limb." Enlarged heart boundaries. Shifted apex.
CaseNotHPOs: HP:0000975
CaseNotHPOFreeText: decreased milk consumption
CasePreviousTesting: NR
Genotyping Method: genomic sequencing.
FunctionalAnalysis: NR
Variant: NM_001276345.2:c.548G>A
ClinVar:43649
CAID:CA004727
gnomAD: NR
AdditionalInfo:
The novel mitochondrial 16S rRNA 2336T>C mutation is associated with hypertrophic cardiomyopathy
PMID: 24367055
Gene: MYH7
HGNC ID: HGNC:7471
Genetic Clues on Implantable Cardioverter-Defibrillator Placement in Young-Age Hypertrophic Cardiomyopathy: A Case Report of Novel MYH7 Mutation and Literature Review
PMID: 35004917
Gene: TPM1
HGNC ID: 12010
A 37-year-old man
Case1: Male, 37 years old, Colombian
DiseaseAssertion: asymmetric septal hypertrophic cardiomyopathy
FamilyInfo: During genetic assessment, a family history of hypertrophic cardiomyopathy (HCM) was detected. The patient’s mother had HCM and died at the age of 66; two living brothers have HCM (51 and 60 years of age). In addition, two of his brothers under the age of 35 died suddenly, two more brothers died from an unknown cause before the age of 5, and yet another brother is being examined for possible heart disease. Findings indicated a dominant inheritance pattern for HCM in this family. Pedigree shown in Figure 2.
ParentalTesting: NR
CasePresentingHPOs: HP:0001639, HP:0001663, HP:0001962, HP:000209, HP:0002315
CaseHPOFreeText: At the age of 25, his symptomatology started, including intense fatigue and mild thoracic pain due to physical activity. At the age of 32, an echocardiogram revealed asymmetric septal hypertrophic cardiomyopathy. The thickness of the interventricular septum was 19.5 mm in the basal third, 22 mm in the middle third, and 23 mm in the apical third, and ventricular tachycardia was also present. Alcohol septal ablation was performed. However, ventricular tachycardia and disabling symptoms persisted, so he required an implantable cardioverter-defibrillator at the age of 35. A routine echocardiogram at the age of 36 yielded the following findings: an LV of normal size, mild hypertrophy of the septum, normal systolic function, and diastolic dysfunction with slow LV relaxation. The patient still suffers dyspnea during physical effort and occasionally thoracic pain with palpitations
CaseNotHPOs: NR
CaseNotHPOFreeText: NR
CasePreviousTesting: NR
Genotyping Method: A molecular panel for HCM including 17 genes was performed using next-generation sequencing. Sanger sequencing chromatogram focusing on the targeted region including the variation
FunctionalAnalysis: NR
Variant: NM_000432.3:c.260G>C
ClinVar: 43461
CAID: CA009968
gnomAD: NR
AdditionalInfo: NR
Genetic variant affecting the myosin light chain 2 related to familial hypertrophic cardiomyopathy
PMID: 33139982
Gene: MYL2
HGNC ID: 7583
Furthering the Link Between the Sarcomere and Primary Cardiomyopathies: Restrictive Cardiomyopathy Associated with Multiple Mutations in Genes Previously Associated With Hypertrophic or Dilated Cardiomyopathy
PMID: 21823217
Gene: MYL3
HGNC ID: 7584
Patient 1
Case#: Patient 1, individual II.1 (Fig. 2A); 22-year-old Salvadoran female
DiseaseAssertion: Restrictive cardiomyopathy (RCM) with advanced heart failure
FamilyInfo: Patient denied a family history of cardiomyopathy, although supporting records were unavailable. Her mother (I.2) was clinically unaffected at age 45 and heterozygous for both MYL3 p.Glu143Lys and MYL2 p.Gly57Glu. Other family members were unavailable for evaluation (Fig. 2A; Table I).
ParentalTesting: Mother (I.2) was confirmed heterozygous for MYL3 c.427G>A (p.Glu143Lys) and MYL2 c.170G>A (p.Gly57Glu). Paternal testing was not reported.
CasePresentingHPOs: HP:0012764 (Orthopnea); HP:0004749 (Atrial flutter); HP:0031295 (Left atrial enlargement); HP:0030718 (right atrial enlargement)
CaseHPOFreeText: Worsening fatigue and exertional dyspnea over 12 months, paroxysmal nocturnal dyspnea, palpitations, NYHA Class III–IV heart failure, and ascites suggestive of congestive hepatopathy. Echocardiography showed severe biatrial enlargement and advanced left ventricular diastolic dysfunction with preserved systolic function. Additional findings included myocardial fibrosis and myofiber disarray on biopsy.
CaseNotHPOs: NR
CaseNotHPOFreeText: At initial presentation, patient denied dizziness, syncope, and lower-extremity edema. No S4 heart sound was detected. Recurrent syncope developed later.
CasePreviousTesting: Targeted sequencing of eight sarcomere genes (ACTC, MYBPC3, MYH7, MYL2, MYL3, TNNI3, TNNT2, TPM1). Genome-wide analysis was not reported. An additional heterozygous MYL2 variant, c.170G>A (p.Gly57Glu), was identified (ClinVar Variation ID: 43458; CAID: CA009910).
Genotyping Method: Sequencing of coding exons and intron–exon boundaries of MYL3 and seven additional sarcomere genes, performed by a commercial CLIA-certified laboratory (Correlagen Diagnostics, Inc.). The specific sequencing platform was not reported.
FunctionalAnalysis: NR
Variant: MYL3 NM_000258.2:c.427G>A (p.Glu143Lys); homozygous
ClinVar: 14063
CAID: CA013774
gnomAD: MYL3 c.427G>A (p.Glu143Lys). Highest reported ancestry-specific allele frequency: 0.0002333 (0.02333%) in the Admixed American population (AC = 14). Overall AF (exomes): 0.000008209; AF (genomes): 0.00001314; AF (total): 0.000008674. https://gnomad.broadinstitute.org/variant/3-46859529-C-T?dataset=gnomad_r4.
AdditionalInfo: Patient developed recurrent syncope and received an implantable cardioverter-defibrillator. She underwent orthotopic heart transplantation six months after RCM diagnosis. Authors considered the homozygous MYL3 and heterozygous MYL2 variants likely contributors to disease, although their individual contributions were not established. Clinical and family findings are reported in Patient 1, Figure 2A, and Table I.
the proband
Case#: Japanese female
DiseaseAssertion: Mild cardiac hypertrophy and asymmetric septal hypertrophy with myocardial hypertrophy increasing.
FamilyInfo: mother and grandmother showed phenotype. Probands mother has the Arg92Trp mutation of TNNT2.
ParentalTesting:not reported
CasePresentingHPOs: HP:0001670
CaseHPOFreeText: not reported
CaseNotHPOs:not reported
CaseNotHPOFreeText:not reported
CasePreviousTesting: DNA analysis
Genotyping Method: Patients with familial HCM
FunctionalAnalysis:not reported
Variant:NM_001276345.2:c.107A>T
ClinVar:not reported
CAID:CA344207376
gnomAD:not reported
AdditionalInfo: pedigree and phenotype associated with Family C.
proband's daughter (C.6)
Case#: Pedigree C, C.6, age 38, Female
FamilyInfo: C.6 is the daughter of C.4 in Pedigree C. C.6 carries the MYBPC3 P910T variant only and does not carry the TNNC1 D145E variant. Normal cardiac screening was reported at age 38.
ParentalTesting: Mother, C.4, carries MYBPC3 P910T and TNNC1 D145E
GenotypingMethod: DNA was isolated from a peripheral blood sample of the patient and was screened for mutations by direct sequencing
FunctionalAnalysis: NR
Variant: NM_000256.3: c.2728C>A (p.Pro910Thr; P910T)
ClinVar: 42656
CAID: CA012881
Pedigree C (C.4)
Case#: Pedigree C, C.4, age 60, Male
DiseaseAssertion: Dilated Cardiomyopathy
FamilyInfo: Pedigree C, Fig. 2 and Table 2. The individual carried MYBPC3 P910T and TNNC1 D145E. A brother was affected with hypertrophic cardiomyopathy. A daughter, C.6, carried MYBPC3 P910T only and had normal cardiac screening at age 38.
CasePresentingHPOs: HP:0200128 HP:0001644
“Dilated cardiomyopathy; left ventricular dilation; severely reduced ejection fraction; left bundle branch block; first-degree atrioventricular block”
Genotyping Method: DNA was isolated from a peripheral blood sample of the patient and was screened for mutations by direct sequencing
Variant: NM_000256.3: c.2728C>A (p.Pro910Thr; P910T)
ClinVar: 42656
CAID: CA012881
12-year-old boy
Case1: Male, 12, China
DiseaseAssertion: Hypertrophic cardiomyopathy
FamilyInfo: parents where not consanguineous, both carried variants.
ParentalTesting: sanger sequencing showed c.1789C>T variant in patients paternal grandmother, and c.3033delG from maternal grandmother
CasePresentingHPOs: HP:0001962 HP:0002094 HP:0001279 HP:0001712 “Palpitations, Dyspnea, Syncope, Left ventricular hypertrophy”
CaseHPOFreeText: symptoms lasted about a year, ECG showed sinus arrhythmia, high left ventricle voltage
CaseNotHPOs: “the patient had no skeletal muscle disease or mental retardation. The diagnosis of glycogen storage disease was also excluded.”
CaseNotHPOFreeText: no other family members diagnosed with heart disease
CasePreviousTesting: diagnosed 3 months before presentation with HCM, no prior genetic testing, but there was echocardiogram and ecg testing.
Genotyping Method: Sanger and NGS
FunctionalAnalysis: no functional analysis preformed
Variant: c.1789C>T (p.Arg597Trp), c.3033delG (p.Gln1012Serfs*8)
ClinVar: NM_000256.3(MYBPC3):c.1789C>T (p.Arg597Trp),
CAID: no results
gnomAD: no results
AdditionalInfo: treated with metoprolol, at 3 moth follow up lvot decreased
Next-generation sequencing (NGS) as a molecular diagnostic tool for hypertrophic cardiomyopathy in a Chinese boy due to novel compound heterozygous mutations in the MYBPC3 gene
PMID: 30896616
Gene: MYBPC3
HGNC ID: HGNC:7551
8 of 570 probands and 25 relatives
Case#: cohort annotation with 8 probands and 25 relatives that are carriers.
DiseaseAssertion: Pathogenic MYBPC3 c.2149–1G>A variant associated with hypertrophic cardiomyopathy
FamilyInfo: Eight unrelated probands, all male, with 45 relatives, 25 where carriers of the variant, 12 had HCM and 13 where unaffected
ParentalTesting: not reported
CasePresentingHPOs: HP:0001712 HP:0002094 HP:0001279 HP:0100749 HP:0001962 HP:0001649 “Left ventricular hypertrophy, Dyspnea, syncope, Chest pain, Palpitations, Tachycardia CaseHPOFreeText:HCM with variable expression with men diagnosed younger then women
CaseNotHPOs:not reported
CaseNotHPOFreeText: not reported
CasePreviousTesting: not reported
Genotyping Method: Sanger sequencing
FunctionalAnalysis: rna analysis shows abnormal transcript, suggesting founder effect.
Variant: MYBPC3 NM_000256.3:c.2149–1G>A
ClinVar: 177814
CAID: not reported
gnomAD:not reported
AdditionalInfo: HCM penetrance increased with age and was highest in males over 30
Founder mutation in myosin-binding protein C with an early onset and a high penetrance in males
PMID: 34588271
Gene: MYBPC3
HGNC ID: HGNC:7551
A94
Case#: A94, male, age 57; Chinese family
DiseaseAssertion: Hypertrophic cardiomyopathy
FamilyInfo: positive family history of cardiomyopathy
CasePresentingHPOs: HP:0001712 HP:0005144
CaseHPOFreeText: Interventricular septal thickness was 16.3 mm
Genotyping Method: Targeted sequencing using the Ion Torrent PGM system with Sanger sequencing confirmation.
Variant: MYBPC3 c.706A>G (p.Ser236Gly), missense
ClinVar: 42786
CAID: CA015725
gnomAD: 0.09513
PMID: 27082122
Gene: TNNT2
HGNC ID: 11949
A total of 28 patients
Case#: 28 patients, 21 retrospectives, 7 prospectives.
DiseaseAssertion: patients had reported unsolved metabolic condition, possible mitochondrial disorder. Onset ranged from prenatal to 7 years, study ranged from 1 year to 29, 9 patients died
FamilyInfo:individual family histories not summerized
ParentalTesting:all reported varients confirmed via sanger sequencing on parents, though most had proband only sequencing.
CasePresentingHPOs: “motor developmental delay, intellectual disability, developmental regression, muscle weakness, dystonia, choreoathetosis, ataxia, tremor, nystagmus, strabismus, Epilepsy, Brain atrophy CaseHPOFreeText: mri showed brain atrophy in 10, white matter injury in 6, hypo/aplasia of the corpus collosum in 3, mitochondrial hypoplasia in 5, myofibular disorganization in 2.
CaseNotHPOs: not reported
CaseNotHPOFreeText: not reported
CasePreviousTesting: retrospective patients had mtdna investigations done without diagnosis
Genotyping Method: WES and Sanger
FunctionalAnalysis: reported for selected finding such as impaired adp/atp transports for a variant slc25a4, no cohort wide analysis
Variant: heterogenous findings across the cohort genes read included SLC25A4, POLG, SPATA5, NDUFB11, SMN1, MYH2, LMNA, TSPOAP1, CACNA1A, ALS2, SCN2A, EPG5, NKX1-2, ATRX, ABCC6, and MYBPC3. Though for the cardiomyopathy purposes, c.1828G > A, p.(Asp610Asn) c.1543_1545delAAC, p.(Asn515del)
ClinVar: 2247822
CAID: not reported
gnomAD: not reported
AdditionalInfo: WES diagnostic yield was 16/28, 4 patients where diagnosed via MD. The paper suggests WES as a first step for children though there where sensitivity limitations.
Effectiveness of whole exome sequencing in unsolved patients with a clinical suspicion of a mitochondrial disorder in Estonia
PMID: 30009132
Gene: MYBPC3, multiple genes, cohort study
HGNC ID: HGNC:7551
Meta-Analysis of Penetrance and Systematic Review on Transition to Disease in Genetic Hypertrophic Cardiomyopathy
PMID: : 37929589
Gene: MYBPC3 ,MYH7 ,TNNT2 ,TNNI3,MYL2, MYL3 TPM1, CSRP3 Multiple genes associated with hypertrophic cardiomyopathy (HCM)
HGNC ID: MYBPC3: HGNC:7551, MYH7: HGNC:7577, TNNT2: HGNC:11949, TNNI3: HGNC:11947, MYL2: HGNC:7576 ,MYL3: HGNC:7584, TPM1: HGNC:12010 CSRP3: HGNC:1430
Case#:: no individual case number
DiseaseAssertion:: Hypertrophic cardiomyopathy (HCM)
FamilyInfo::Familial HCM cohorts and at-risk relatives carrying pathogenic or likely pathogenic sarcomeric variants were investigated. Pooled penetrance among non-proband variant-carrying relatives was 57%
ParentalTesting:: No individual parental segregation or parental testing information reported.
CasePresentingHPOs:: Left ventricular hypertrophy
CaseHPOFreeText:: Hypertrophic cardiomyopathy characterized by unexplained left ventricular hypertrophy.
CaseNotHPOs:: N/A
CaseNotHPOFreeText:; N/A
CasePreviousTesting::N/A
Genotyping Method::N/A
FunctionalAnalysis::N/A
Variant:: No specific nucleotide or protein-level variant reported as the subject of an individual case.
ClinVar:: N/A
CAID:: N/A
gnomAD:: N/A
AdditionalInfo:
The proband was a 63-year-old woman who presented to the outpatient department in July 2025 with a 7-day history of palpitations. She had been admitted to a local hospital seven days earlier due to sudden-onset palpitations.
Case#: Single proband ; 63-year-old female; palpitations at presentation July 2025; HCM diagnosis established at age 63
DiseaseAssertion: Hypertrophic cardiomyopathy (HCM) complicated by apical left ventricular aneurysm and mid-ventricular obstruction
FamilyInfo: No family history of cardiac disease or sudden cardiac death at a young age reported. Both parents deceased (one of cancer, one of natural causes at age 92), neither with reported cardiovascular disease; proband has no siblings. Only first-degree relative is her son, who carries the KCNJ5 c.464G>A variant but not the MYBPC3 c.278delA variant, and has a normal echocardiogram with no myocardial hypertrophy. No pedigree beyond the son (Fig. 3B).
ParentalTesting: Not performed; both parents deceased, no DNA available; authors state a valid familial segregation analysis could not be performed. Only one family member (son) was available for cascade Sanger screening.
CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy); HP:0001649 (Tachycardia), palpitations; HP:0001712 (Left ventricular hypertrophy).
CaseNotHPOFreeText: No history of hypertension, diabetes, or hyperlipidemia. Phenocopies excluded: no extra-cardiac manifestations of Fabry disease and GLA testing negative; cardiac amyloidosis excluded (no apical sparing, normal serum free light chains, negative serum protein electrophoresis and immunofixation); no significant coronary stenosis on coronary CT angiography. No QT prolongation or features of Andersen–Tawil syndrome on ECG.
CasePreviousTesting: Whole exome sequencing identified both variants; all rare and known variants validated by Sanger sequencing, with cascade Sanger screening in available one family member. No prior genetic testing reported before this episode.
Genotyping Method: Targeted region capture with next-generation high-throughput sequencing (whole exome, exonic plus flanking regions); variants confirmed by bidirectional Sanger sequencing. Cascade screening by Sanger in the son. MYBPC3 variant absent from 1000 Genomes, ESP6500, ExAC, and the Besuper local database. KCNJ5 variant absent from 1000 Genomes and ESP6500, ExAC frequency, absent from local Basenhall controls.
FunctionalAnalysis: None performed; authors list absence of functional studies and lack of mRNA-level validation as limitations. MYBPC3 frameshift predicted to trigger nonsense-mediated decay.
Variant: MYBPC3 NM_000256.3:c.278delA (p.Lys93ArgfsTer3); heterozygous; exon 2; novel, not in ClinVar or HGMD; classified Likely Pathogenic by ACMG (PVS1, PM2). Second variant: KCNJ5 NM_000256.3:c.464G>A (p.Arg155Gln); heterozygous; exon 2; novel, not in ClinVar or HGMD; classified VUS (PM2, PP3). Note the paper's KCNJ5 accession is written as NM_000256.3, which is the MYBPC3 transcript, most likely a typo in the article Pepper please conform for me the correct KCNJ5 accession
ClinVar: No ClinVar record for either variant; nearby KCNJ5 missense variants c.451G>A, c.452G>A, c.470T>G, and c.473C>G are documented as pathogenic/likely pathogenic for long QT syndrome or aldosteronism, and downstream frameshift/nonsense variants at the MYBPC3 locus are classified pathogenic or likely pathogenic.
CAID:Not found.
gnomAD: No allele frequency available, so no MAF to report.
PMID: 42428486
Gene: MYBPC3
HGNC: HGNC:7551
AdditionalInfo:Single-case report, no case numbering system used. Treated with dapagliflozin, metoprolol, rivaroxaban, and recombinant human BNP for 13 days, discharged on the first three; mexiletine added at 1-week follow-up for persistent palpitations. ICD recommended but declined due to financial constraints; 3-month follow-up showed good adherence with occasional palpitations and no serious arrhythmic events. Authors conclude MYBPC3 c.278delA is likely pathogenic for HCM, while the KCNJ5 variant shows no clinical phenotype in the proband or her son and may be incidental or a modifier.
A 27-year-old man
Case#:1 Male, 27, no reported ethnicity
DiseaseAssertion: sinus tachycardia, signs of hypertrophy of both atria and ventricles
FamilyInfo: proband had a sister who died at 15 days of age due to a congenital heart disease (transposition of the great arteries). No other relative was diagnosed with cardiomyopathy of other cardiac disease before 50 years of age
ParentalTesting: family history was unremarkable. Parents were not consanguineous.
CasePresentingHPOs: HP:0001639, HP:0001644, HP:0200128, HP:0004308 "Hypertrophic cardiomyopathy, Dilated cardiomyopathy, Biventricular hypertrophy, Ventricular arrhythmia <br /> CaseHPOFreeText: Dilated cardiomyopathy recorded at age of 4, Severe respiratory infection led to circulatory decompensation and acute femoral thrombosis"
CaseNotHPOs: none reported
CaseNotHPOFreeText: no evidence of myeloproliferative disease was found when bone marrow trepanobiopsy was preformed.
CasePreviousTesting: dcm diagnosis at age 4, Whole exome sequencing (WES)
Genotyping Method: WES, NGS, & Sanger
FunctionalAnalysis: none reported
Variant: chr11:g.47357432_47357458del, ENST00000545968.1: c.2711_2737del, p.2711_2737del
ClinVar: VCV000978729.2
gnomAD: ENSG00000134571.12
Mixed Hypertrophic and Dilated Phenotype of Cardiomyopathy in a Patient With Homozygous In-Frame Deletion in the MyBPC3 Gene Treated as Myocarditis for a Long Time
33101033
MyBPC3
HGNCID:7551
Case report: Severe arrhythmogenic cardiomyopathy in a young girl with compound heterozygous DSG2 and MYBPC3 variants with a 6-year follow-up
PMID: : 40115818
Gene: :DSG2 , MYBPC3
HGNC ID: :DSG2: HGNC:3049, MYBPC3: HGNC:7551
Genetic Variants Are Not Rare in ICD Candidates with Dilated Cardiomyopathy: Time for Next-Generation Sequencing?
PMID: 31179125
Gene: TPM1
HGNC ID: 12010
Von Hippel-Lindau disease type 2 in a Chinese family with a VHL p.W88X truncation
PMID: 25069792
Gene: VHL
StandardizedReferenceSequence: NM_000551.3
PatientID: None
KindredID: 49
Case: F, 15Y0M, Ethnicity Unknown
DiseaseAssertion: VHL
FamilyInfo: N/A
CohortInfo: A total of 190 patients recruited by the COMETE network over 15 years were included in the study.
CasePresentingHPOs: HP:0002666 (pheochromocytoma)
CaseHPOFreeText: The patient had one benign pheochromocytoma.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: RET, SDHB, SDHC, SDHD
PreviouslyPublished: N/A
SupplementalData: Patient information was extracted from Table 1 of Supplementary.
Variant: p.R167Q (c.500G>A)
LegacyVariant: N/A
CaseProblemVariantFreeText: N/A
ClinVar: 2216 https://www.ncbi.nlm.nih.gov/clinvar/variation/2216/
CAID: N/A
gnomAD: 0.000003977 https://gnomad.broadinstitute.org/variant/3-10191507-G-A
VariantEvidence:N/A
MutationType: missense_variant;transition
CivicName: R167Q (c.500 G >A)
MultipleGeneVariants: N/A
PatientID: None
KindredID: 51
Case: M, 41Y0M, Ethnicity Unknown
DiseaseAssertion: VHL
FamilyInfo: N/A
CohortInfo: A total of 190 patients recruited by the COMETE network over 15 years were included in the study.
CasePresentingHPOs: HP:0002666 (pheochromocytoma)
CaseHPOFreeText: The patient had one benign pheochromocytoma.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: RET, SDHB, SDHC, SDHD
PreviouslyPublished: N/A
SupplementalData: Patient information was extracted from Table 1 of Supplementary.
Variant: p.Y175* (c.525C>G)
CaseProblemVariantFreeText: The protein change was written as Thr175 in the Supplemental but the nucleotide change corresponds to Tyr175.
LegacyVariant: N/A
ClinVarID: 182974 https://www.ncbi.nlm.nih.gov/clinvar/variation/182974/
CAID: N/A
gnomAD: N/A
VariantEvidence: N/A
MutationType: stop_gained
CivicName: Y175* (c.525C>G)
MultipleGeneVariants: N/A
Next-generation sequencing in familial breast cancer patients from Lebanon
PMID: 28202063
Gene: VHL
StandardizedReferenceSequence: NM_000551.3
GroupID/ KindredID: F15
Case: Sex unknown, 32Y0M, Spanish
DiseaseAssertion: assumed VHL
FamilyInfo: Noted of familial antecedents of phaeochromocytoma.
CasePresentingHPOs: HP:0002666 (pheochromocytoma)
CaseHPOFreeText: Unilateral pheo. Age of onset is 32Y0M.
CaseNotHPOs: HP:0006770; HP:0000107; HP:0006880; HP:0001737; HP:0009711 (clear cell renal cell carcinoma, renal cysts, cerebellar hemangioblastoma, pancreatic cysts, retinal capillary hemangioma)
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: N/A
Variant: p.Y175C (c.524A>G)
LegacyVariant: N/A
CaseProblemVariantFreeText: N/A
ClinVarID: 36905 https://www.ncbi.nlm.nih.gov/clinvar/variation/36905/
CAID: N/A
gnomAD: N/A
VariantEvidence: N/A
MutationType: missense_variant; transition
CivicName: Y175C (c.524A>G)
MultipleGeneVariants: N/A
35 (45%) had missense variant
PatientID: 29
KindredID: 29
Case: Sex Unknown, Age Unknown, Ethnicity Unknown
DiseaseAssertion: VHL
FamilyInfo: N/A
CasePresentingHPOs: HP:0010797; HP:0006770; HP:0009711 (hemangioblastoma; clear cell renal cell carcinoma; retinal capillary hemangioma)
CaseHPOFreeText: N/A
CaseNotHPOs: HP:0100634; HP:0030405; HP:0030421 (Neuroendocrine neoplasm, pancreatic neuroendocrine neoplasm, Epididymal neoplasm)
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: Yes; see table S1 for VHL subject genetic and manifestation information.
Variant: p.P86L (c.257C>T)
LegacyVariant: p.P157L (c.470C>T)
CaseProblemVariantFreeText: converted from legacy notation c.470C>T; Pro157Leu; authors contacted
ClinVarID: 182977 https://www.ncbi.nlm.nih.gov/clinvar/variation/182977/
CAID: N/A
gnomAD: N/A
VariantEvidence: N/A
MutationType: missense_variant; transition
CivicName: P86L (c.257C>T)
MultipleGeneVariants: N/A
VHL c.505 T>C mutation confers a high age related penetrance but no increased overall mortality
PMID: 11483638
Gene: VHL
StandardizedReferenceSequence: NM_000551.3
PatientID: None
KindredID: 26
Case: Sex Unknown, Age Unknown, Japanese
DiseaseAssertion: VHL
FamilyInfo: N/A
CasePresentingHPOs: HP:0010797; HP:0009711; HP:0005584 (Hemangioblastoma, Retinal capillary hemangioma, Renal cell carcinoma)
CaseHPOFreeText: CNS hemangioblastoma, retinal angioma and renal cell carcinoma.
CaseNotHPOs: HP:0001732 (Abnormality of the pancreas)
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: 8634692 (variants differ by one base pair; unclear which is accurate)
SupplementalData: N/A
Variant: p.D143Efs*13 (c.429_438del)
LegacyVariant: c.642del10bp
CaseProblemVariantFreeText: N/A
ClinVarID: N/A
CAID: CA2573131814, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA2573131814
gnomAD: N/A
VariantEvidence: N/A
MutationType: deletion; minus_1_frameshift_variant
CivicName: D143Efs*13 (c.429_438del)
MultipleGeneVariants: N/A
Figure 6. Functional study of synonymous mutations in VHL E2. (A) Functional hypoxia response element (HRE)–dependent reporter assays were performed in 786-O cells to evaluate the impact of VHL mutations in E2 (P138L and G144R) on VHL protein activity. The VHL protein lacking E2 (pVHL172/VHLΔE2) was used as a negative control. The results are expressed as firefly luciferase activity relative to Renilla luciferase as an internal control; 1.0 unit denotes the basal activity of endogenous HIF-2α using the HRE luciferase reporter plasmid. Immunoblots using an antibody specific for the hemagglutinin tag (HA) were used to detect HA-VHL. (B) Characterization of VHL E2 skipping by minigene analyses. Minigene experiments were performed in a variety of cell lines relevant to the studied diseases: renal (293T, 786-O, and HK2), pheochromocytoma (pheo; PC12), erythroid cell line (UT7 cultured with erythropoietin), and LCL. RT-PCR was performed on mRNA obtained from cell lines transfected with a minigene construct containing VHL E2 flanked by intronic sequences cloned between the SERPING1 exons (exons A and B; targeted by the RT-PCR primers). Bands corresponding to EA and EB spliced together or with VHL E2 are indicated on the right. (C) Sashimi plots from RNA-seq data. The positions of the different VHL exons are indicated, with the maximum number of reads for each exon indicated at the right. Splice junctions are denoted by the horizontal links, with details provided in supplemental Figure 15A. (D) Heatmap of pheochromocytoma transcriptome data. A comparison of transcriptome data for the pheochromocytoma from patient F11 III.1 (with P138P mutation) vs Affymetrix data from the largest available cohort of paragangliomas/pheochromocytomas (recruited by the French COMETE network) that identified homogeneous molecular subgroups associated with susceptibility genes (Burnichon et al30).
F1, II.1c.429C>T/c.340+770T>CVHL p.Asp143Asp/X1 p.Ser179Pro?1991/15 yM16.6576.9163Erythrocytosis, kidney ischemic infarct—
PatientID: II.1
KindredID: F1
Case: M, 15Y0M, Ethnicity Unknown
DiseaseAssertion: Polycythemia
FamilyInfo: N/A
CasePresentingHPOs: HP:0001901 (Polycythemia)
CaseHPOFreeText: Diagnosed with erythrocytosis (Polycythemia) and kidney ischemic infarct at age 15 (DOB: 1991).
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: N/A
Variant: c.340+770T>C
LegacyVariant: N/A
CaseProblemVariantFreeText: N/A
ClinVarID: 816685, https://www.ncbi.nlm.nih.gov/clinvar/variation/816685/
CAID: N/A
gnomAD: N/A
VariantEvidence: Variants are heterozygous.
MutationType: missense_variant;transition; splice_site_variant
CivicName: D143= (c.429C>T) and c.340+770T>C
MultipleGeneVariants: Germline, VHL, c.429C>T (p.Asp143Asp)
c.429C>T/c.429C>T
The authors identify a new VHL cryptic exon (termed E1') deep in intron 1 that is naturally expressed in many tissues. Mutations in E1' are identified in 7 families with erythrocytosis and in 1 large family with typical VHL disease but without any alteration in the other VHL exons. In this study, the authors show that the mutations in E1' induced a dysregulation of VHL splicing with excessive retention of E1' and were associated with a downregulation of VHL protein expression. Patient II.1 (family F9) was found to have the germline variant D143= (c.429C>T). The patient was diagnosed with erythrocytosis at 5 months old (DOB: 1997). This variant is homozygous in the patient. This patient was also found to have the HB Sitia germline variant. Both asymptomatic parents were genetically sequenced and found to be carriers of the variant. Patient II.1 (family F10) was also found to have this variant. This patient was diagnosed with erythrocytosis (Polycythemia) and splenomegaly at 4.5 years old (DOB: 2002). This patient was also found to have the Beta Thalassemia germline variant. This patient’s asymptomatic patients were both found to be carriers of the same variant in VHL. Their other child (II.2) also carried the gene. Patient II.1 was the only one who was homozygous for the variant.
Retinal abnormalities associated with a mutation of the nucleotide 683 in von Hippel-Lindau disease
PMID: 10955664
Gene: VHL
StandardizedReferenceSequence: NM_000551.3
PMID: 29813026
Germline sequencing of the VHL gene was performed on patients who presented with VHL syndromic hemangioblastomas, and germline results were compared to sequencing results from matched tumor tissue samples. Patients were only identified by their tumor sample number. Sample 3 (patient 3) had a Glu94Lys missense mutation (c.280G>A) in the VHL gene. Genetic analysis was conducted as follows: peripheral blood samples were collected from patients, and genomic DNA was extracted, amplified, and purified using ExoSAP IT (ExoSAP IT (Thermo Scientific Inc., MA, USA). Sanger sequencing was performed on samples (Bigdye direct cycle sequencing v3.1, Life Technologies, CS, USA) and capillary electrophoresis was performed on an ABI Genetic Analyzer (ABI 3130xl, Life technologies, CS, USA). Deletion and duplication analysis of the VHL gene spanning the chr3p.25.3 locus was tested by the Multiplex Ligation-dependant Probe Amplification (MLPA) procedure. VHL gene locus-specific probes (P016-C2 VHL) were purchased from MRC Holland (MRC Holland, Amsterdam, Netherlands). ACMG evidence codes: PP4- Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.
VHL germline variants
Pathogenic variants from 10,389 individuals across 33 cancer types were examined from The Cancer Genome Atlas (TCGA) cohort. 12 of these individuals had a germline mutation in the VHL gene. The Y98H (c.292T>C) missense VHL mutation was found in three white males aged 65Y0M, 31Y0M, and 23Y0M, who were all diagnosed with either pheochromocytoma and paraganglioma. No family information was provided for any of the patients.
583FemaleIYesAGND* AGLOH (G)
PatientID: 5
KindredID: 5
Case: F, 83Y0M, Taiwanese (East-Asian)
DiseaseAssertion: renal cell carcinoma
FamilyInfo: N/A
CohortInfo: 7 of 19 patients presenting with clear cell renal cell carcinoma were found to be heterozygous for the germline variant rs779805 (c.-195G>A) in VHL. All of these patients also presented with the germline variant rs1642742 in VHL (c.*294G>A).
CasePresentingHPOs: HP:0006770 (clear cell renal cell carcinoma)
CaseHPOFreeText: She had stage I clear cell renal cell carcinoma
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: 21982469
SupplementalData: Yes - Additional file 1: Figure S1
Variant: c.-195G>A
LegacyVariant: N/A
CaseProblemVariantFreeText: N/A
ClinVarID: 342397 https://www.ncbi.nlm.nih.gov/clinvar/variation/342397
CAID: N/A
gnomAD: 0.5796 https://gnomad.broadinstitute.org/variant/3-10183337-G-A
VariantEvidence: RFLP analysis was used to screen for the allele genotype by BsaJ I digestion methods. Heterozygous for both, she also presented with the germline variant c.*294G>A in VHL. LOH (G) of rs1642742 was found in the tumor tissue as well
MutationType: 5_prime_UTR_variant
CivicName: c.-195G>A AND c.*294G>A
MultipleGeneVariants: Germline, VHL, c.*294G>A
Genomic DNA samples were extracted from 10 mL of ethylenediaminetetraacetic acid (EDTA)-treated peripheral blood samples using the Nucleosopin Blood Mini Kit (MACHEREY–NAGEL GmbH & Co. KG, Düren, Germany) according to the manufacturer’s instructions. The following seven genes were analysed: MAX ({"type":"entrez-nucleotide","attrs":{"text":"NM_002382.5","term_id":"1653960896","term_text":"NM_002382.5"}}NM_002382.5), SDHB ({"type":"entrez-nucleotide","attrs":{"text":"NM_003000.3","term_id":"1732746310","term_text":"NM_003000.3"}}NM_003000.3), SDHC ({"type":"entrez-nucleotide","attrs":{"text":"NM_003001.5","term_id":"1779948875","term_text":"NM_003001.5"}}NM_003001.5), SDHD ({"type":"entrez-nucleotide","attrs":{"text":"NM_003002.4","term_id":"1519245278","term_text":"NM_003002.4"}}NM_003002.4), TMEM127 ({"type":"entrez-nucleotide","attrs":{"text":"NM_017849.4","term_id":"1777425445","term_text":"NM_017849.4"}}NM_017849.4), VHL ({"type":"entrez-nucleotide","attrs":{"text":"NM_000551.3","term_id":"319655736","term_text":"NM_000551.3"}}NM_000551.3), and exons 10, 11 and 13–16 of the RET ({"type":"entrez-nucleotide","attrs":{"text":"NM_020630.4","term_id":"126273513","term_text":"NM_020630.4"}}NM_020630.4) proto-oncogene. A priority order was used for genetic analysis according to previous recommendations [5,6]. For instance, VHL and RET genes were analysed with priority for bilateral PCC, SDHB gene for retroperitoneum PGL or metastatic PCC/PGL, and SDHD gene for head and neck PGL. When a pathogenic variant was found in one of these genes, no further testing was performed in the remaining genes. After performing PCR using gel electrophoresis for each primer pair, Sanger sequencing was outsourced to a commercial service provider (Eurofins Genomics, Ota-ku, Tokyo, Japan) to detect variants, and the results were analysed at our department. The primers used for the PCR amplification are listed in Table S5. When no P/LP variant was found by the Sanger sequencing, all exons of the SDHB, SDHC, and SDHD gene were reanalysed using multiplex ligation-dependent probe amplification (MLPA) to examine copy number variation. The MLPA assay was carried out by a commercial service provider (FALCO Biosystems Ltd., Kumiyama, Kyoto, Japan). The sequence results were analysed using Sequence Scanner Software v2.0 (Thermo Fisher Scientific, Waltham, MA, USA) and CLC Sequence Viewer 8.0 software (QIAGEN, Aarhus C, Denmark).
ArticleReferenceSequence: NM_000551.3
GenotypingMethod: Seven genes were analysed (MAX, SDHB, SDHC, SDHD, TMEM127, VHL, and exons 10, 11 and 13–16 of RET. After PCR for each primer pair, Sanger sequencing was outsourced to detect variants, followed by the analysis of the results internally.
SamplingMethod: peripheral blood
Somatic mutations of von Hippel-Lindau (VHL) tumor-suppressor gene in european kidney cancers
PMID: 7591282
Gene: VHL
StandardizedReferenceSequence: NM_000551.3
third family with a VHL type 1 disease carried a c.475T>C/p.Trp88Arg exchange.
PatientID: CV2
KindredID: C
Case: M, 12Y0M, Serbian
DiseaseAssertion: Asymptomatic
FamilyInfo: Families were selected based on their clinical data and family history. Patient and his sister (CV1) are both currently asymptomatic, but possess the same variant as their father (CIV2), who was diagnosed with retinal hemangioblastoma at 12Y0M. Then, multiple pancreatic and kidney cysts were detected at 29Y0M and left kidney cancer was found at age 35Y0M. Patient’s grandfather, great grandfather and great uncle (CIII1; CII1, CII2) had retinal capillary hemangioma, CNS hemangioblastoma and renal cell carcinoma. Out of the three of them, only the great grandfather had genetic testing performed and was found to have the same mutation as the patient. See pedigree in figure 1.
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: N/A
Variant: p.W88R (c.262T>A)
LegacyVariant: p.W88R (c.475T>A)
CaseProblemVariantFreeText: N/A
ClinVarID: 456577, https://www.ncbi.nlm.nih.gov/clinvar/variation/456577/
CAID: N/A
gnomAD: N/A
VariantEvidence: N/A
MutationType: missense variant; transversion
CivicName: W88R (c.262T>A)
MultipleGeneVariants: N/A
Genetic testingThe proband’s maternal aunt, who lived a significant distance away had genetic testing; no pathogenic mutation was detected in either BRCA 1 or BRCA2 genes. A variant identified in the VHL gene c.74C>T(p.Pro25Leu) was thought to be pathogenic at the time, and the extended family was advised that family testing was available. On this basis, our proband was offered testing for the family-specific variant. The DNA sample obtained from the patient was independently amplified and sequenced in opposite directions from exon 1 of the VHL gene. Analysis of this exon has not detected the c.74C>T variant. Soon thereafter, this variant was revised as unlikely to be pathogenic.Subsequently, his aunt had next-generation sequencing (NGS) for MAX, RET, SDHAF2, SDHB, SDHC, SDHD, TMEM127 and multiplex ligation-dependent probe amplification (MLPA) for VHL, SDHA, MAX, SDHB, SDHC and SDHC. No pathogenic mutation was detected.Our proband was offered MLPA and NGS for VHL and TP53. Complete sequence screening of all coding exons and intron–exon boundaries of the TP53 gene did not reveal the presence of a pathogenic variant. In MLPA, none of the tested exons showed a significant deviation from the normal range of the tested population, and duplicate tests were concordantly indicating a normal copy number.Following his disease progression and with the recent diagnosis of papillary thyroid cancer as well as papillary urothelial cancer and the availability of broader panel testing, testing of72 cancer predisposition genes was offered for him. The heterozygous pathogenic variant, CHEK21100delC was found.
ArticleReferenceSequence: Not specified – Assumption: variants assumed to have been documented by the author under reference sequence NM_000551.3
GenotypingMethod: next-generation sequencing (NGS) for MAX, RET, SDHAF2, SDHB, SDHC, SDHD, TMEM127 and multiplex ligation-dependent probe amplification (MLPA) for VHL, SDHA, MAX, SDHB, SDHC and SDHC.
SamplingMethod: N/A
Familial pheochromocytomas and paragangliomas: stories from the sign-out room
PMID: 17525482
Gene: VHL
StandardizedReferenceSequence: NM_000551.3
PatientID: 63
KindredID: N/A
Case: Sex Unknown, Age Unknown, Ethnicity Unknown
DiseaseAssertion: VHL
FamilyInfo: N/A
CohortInfo: The authors evaluated 64 VHL patients (32 women and 32 men) with renal involvement of whom 54/64 had undergone renal surgery or a radiofrequency thermal ablation procedure for RCC. In 10/64 VHL patients, at least one or more RCC were diagnosed, however at the time of diagnosis an indication for treatment was not yet present. For all patients several CT/MRI scans existed for retrospective description of tumour growth kinetics.
CasePresentingHPOs: HP:0005584 (Renal cell carcinoma)
CaseHPOFreeText: This is a tumor resolution study (VHL patients were investigated based on the presence of renal tumors.) No other phenotypic information is available.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: Supplementary Table S2 describes 9 patients with nonsense mutations, including this patient.
Variant: p.R161* (c.481C>T)
LegacyVariant: c.694C>T
CaseProblemVariantFreeText: N/A
ClinVarID: 2217, https://www.ncbi.nlm.nih.gov/clinvar/variation/2217/
CAID: N/A
gnomAD: N/A
VariantEvidence: N/A
MutationType: stop_gained
CivicName: R161* (c.481C>T)
MultipleGeneVariants: N/A
Case studies of three families affected by VHL and their children were described. The legacy mutation C712T in VHL was found in three members of family 1. The father was 48Y when he was found to have renal cell carcinoma and bilateral pheochromocytoma after initially presenting with loin pain, pyrexia and haematuria. He died one year after diagnosis despite chemotherapy treatments. His son was diagnosed with and treated for bilateral pheochromocytoma at 13Y and endolymphatic sac tumors at 19Y after noting tinnitus, increasing hearing difficulties in his left ear since the age of 16. The son had a sister who tested positive for the mutation and appears to be asymptomatic. It is unclear whether the mother and the second son were negative for the mutation or were not tested.
PatientID: None
KindredID: 36
Case: M, 31Y0M, Spanish
DiseaseAssertion: VHL
FamilyInfo: Positive for familial antecedents. No known familial tumors.
CohortInfo: Probands belonging to 18 unrelated Spanish VHL families carrying germline VHL deletions.
CasePresentingHPOs: HP:0006880; HP:0001737 (Cerebellar hemangioblastoma, Pancreatic cysts)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: N/A
Variant: Exon 1 Deletion (c.1-?_340+?del)
LegacyVariant: N/A
CaseProblemVariantFreeText: N/A
ClinVarID: N/A
CAID: N/A
gnomAD: N/A
VariantEvidence: Germline HSPC300, ENST197804 and FANCD2 (unclear if partial or complete) gene deletions. Study provides evidence to show that loss of HSPC300 highly correlates with the absence of ccRCC in VHL patients.
MutationType: exon_loss_variant
CivicName: Exon 1 Deletion
MultipleGeneVariants: Germline, HSPC300, Deletion MultipleGeneVariants: Germline, ENST197804, Deletion MultipleGeneVariants: Germline, FANCD2, Deletion
ProbandFemale
PatientID: 2
KindredID: 2
Case: F, 50Y0M, Chinese
DiseaseAssertion: VHL
FamilyInfo: See figure 3 for pedigree. In family 2, the proband (Patient 2 in the paper) was a 50 year old female who presented with bilateral renal cell carcinoma, pancreatic neuroendocrine tumor, and a renal cyst. The proband's sister was diagnosed with a pancratic NET and died of a hemorrhagic stroke at 40 years of age. Their mother also died of a stroke at 50 years of age. Genetic analysis revealed a c.232A>T (p.Asn78Tyr) mutation in the VHL gene of the proband. Based on her clinical presentation and family history, the proband was diagnosed with VHL type 1. Sanger sequencing on her family members detected the same mutation in her mother, sister, brother, and nephew.The proband's brother and nephew refused further VHL-related examination.
CasePresentingHPOs: HP:0005584, HP:0030405, HP:0000107 (renal cell carcinoma, pancreatic endocrine tumor, renal cyst)
CaseHPOFreeText: Referred to hospital in August 2011 for masses in her left kidney. The CT scan showed several masses in her left kidney and the largest one was about 3.1 × 2.4 cm. She underwent a radical nephrectomy 5 years ago for the tumor in her right kidney.
CaseNotHPOs:None
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: N/A
Variant: p.N78Y (c.232A>T)
LegacyVariant: N/A
CaseProblemVariant Free Text: N/A
ClinVar: 223167, https://www.ncbi.nlm.nih.gov/clinvar/variation/223167/
CAID: N/A
gnomAD: N/A
VariantEvidence: N/A
MutationType: missense_transversion
CivicName: N78Y (c.232A>T)
MultipleGeneVariants: N/A
VCB0.04T VHL RTK2 0.57
PatientID: VCB.04T
KindredID: 5
Case: Sex Unknown, 24Y0M, Ethnicity Unknown
DiseaseAssertion: pheochromocytoma
FamilyInfo: N/A
CasePresentingHPOs: HP:0002668; HP:0002666 (paraganglioma, pheochromocytoma)
CaseHPOFreeText: Presented with bilateral pheochromocytoma
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: MAX, RET, SDHA, SDHB, SDHC, SDHD, TMEM127
PreviouslyPublished: 25545346 (see table S1 and S10)
SupplementalData: Yes
Variant: p.V166Dfs*9 (c.480_481insCGATGCCTCCAGGT)
LegacyVariant: N/A
CaseProblemVariantFreeText: N/A
ClinVarID: N/A
CAID: CA2573119327 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA2573119327
gnomAD: N/A
VariantEvidence: N/A
MutationType: plus_2_frameshift_variant
CivicName: V166Dfs*9 (c.480_481insCGATGCCTCCAGGT)
MultipleGeneVariants: N/A
PatientID: None
KindredID: 1
Case: F, Age Unknown, Ethnicity Unknown
DiseaseAssertion: VHL
FamilyInfo: This patient's fourth oldest sister had bilateral retinal angiomas, metastatic islet cell cancer, liver lesions, pancreatic endocrine tumours, and cerebellar hemangioblastoma. Her third oldest sister had a pancreatic head tumour and bilateral renal cysts. Her youngest sister had bilateral angiomas, liver lesions, and metastatic islet cell cancer. The oldest sister did not carry the mutation or have any abnormal presentations. The patient's mother was found to harbor the mutation and had retinal angiomas, bilateral adrenal pheochromocytoma, and pancreatic cysts. The patient's maternal grandmother was suspected to have VHL as she developed progressive blindness at age 32 and was completely blind by age 36. She died at age 68 due to an acute hemorrhage into and around a vascular tumour. The patient's maternal aunt died suddenly at age 51 due to a cerebellar hemangioblastoma. One of the aunt's children died at age 25 due to a cerebellar hemangioblastoma and another had bilateral retinal angiomas and multiple pancreatic cysts. Refer to Figure 1 for pedigree.
CasePresentingHPOs: HP:0030405, HP:0000107, HP:0000138 (pancreatic endocrine tumour, Renal cyst, Ovarian cyst)
CaseHPOFreeText: The patient initially only presented with bilateral small ovarian cysts. On follow up four years later, it was found that she had two hypervascular pancreatic head tumours <1cm in diameter, a complex left renal cyst, and enlarged ovarian cysts. A pancreaticoduodenectomy and left heminephrectomy was performed, revealing two <1-cm islet cell tumours and a complex renal cyst with severe cellular atypia but no invasive maligancy.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: N/A
Variant: c.R167Q (c.500G>A)
LegacyVariant: c.R167Q (c.713G>A)
CaseProblemVariantFreeText: N/A
ClinVarID: 2216 https://www.ncbi.nlm.nih.gov/clinvar/variation/2216/
CAID: N/A
gnomAD: 0.000003977 https://gnomad.broadinstitute.org/variant/3-10191507-G-A
VariantEvidence: N/A
MutationType: missense_variant;transition
CivicName: R167Q (c.500G>A)
MultipleGeneVariants: N/A
VHL-25c.1 − ?_463 + ?Del ex 1 + 2[11]noA2Multiple–+––Renal
PatientID: VHL-25
KindredID: 25
Case: Sex Unknown, Age Unknown, Italian
DiseaseAssertion: VHL
FamilyInfo: No family history of VHL.
CohortInfo: Forty-three index cases were referred to the Service of Medical Genetics, Genova, for germline mutation analysis in the VHL gene between 1995 and 2008.
CasePresentingHPOs: HP:0010797; HP:0000107; HP:0001732 (Hemangioblastoma, Renal cyst, Abnormality of the pancreas)
CaseHPOFreeText: Multiple CNS hemangioblastomas. Clinical classification: A2.
CaseNotHPOs: HP:0002666; HP:0005584; HP:0009711 (Pheochromocytoma, Renal cell carcinoma, Retinal capillary hemangioma)
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: N/A
Variant: Exon 1-2 Deletion (c.1-?_463+?del)
LegacyVariant: N/A
CaseProblemVariantFreeText: N/A
ClinVarID: N/A
CAID: N/A
gnomAD: N/A
VariantEvidence: N/A
MutationType: exon_loss_variant
CivicName: Exon 1-2 Deletion
MultipleGeneVariants: N/A
both brothers with renal cell carcinoma with VHL gene mutation
PatientID: None (Brother 2)
KindredID: 1
Case: M, 70Y0M, Ethnicity Unknown
DiseaseAssertion: VHL
FamilyInfo: One brother (proband, 75Y) presented with Hemangioblastoma, Hypertension, Cataract, Visual loss, Amblyopia, Diabetes mellitus, Adenocarcinoma of the colon, Clear cell renal cell carcinoma, Retinitis, Anal canal adenocarcinoma, Spinal hemangioblastoma, Gastrointestinal carcinoma, Cerebellar hemangioblastoma and the same VHL mutation as this patient. Mother with a brain tumor of unconfirmed pathology, and another brother (79Y) with renal cell carcinoma with the VHL gene mutation. Nephew (44Y) VHL mutation but is asymptomatic. Niece (40Y) had a brain hemorrhage, daughter had hematologic malignancy, nephew has pancreatic cancer; genetic information is unclear or not provided for either.
CasePresentingHPOs: HP:0005584 (Renal cell carcinoma)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: Figure 1
Variant: p.E70K (c.208G>A)
LegacyVariant: N/A
CaseProblemVariantFreeText: N/A
ClinVarID: 43598, https://www.ncbi.nlm.nih.gov/clinvar/variation/43598/
CAID: N/A
gnomAD: 0.000004365, https://gnomad.broadinstitute.org/variant/3-10183739-G-A
VariantEvidence: N/A
MutationType: missense_variant;transition
CivicName: E70K (c.208G>A)
MultipleGeneVariants: N/A