A retrospective cohort study included all the VHL patients diagnosed at Peking University First Hospital (Beijing, China) prior to June 1 2016. A total of 291 patients from 115 different families were included for analysis. This familial mutation was confirmed in family #52 with 9 affected members who were all genetically confirmed with the mutation. A male proband was diagnosed with CNS hemangioblastoma at 28Y, RCC at 28Y, and multiple pancreatic lesions at 28Y. His son and daughter of unknown ages are asymptomatic. His mother was diagnosed with CNS hemangioblastoma at 66Y, RCC at 69Y, and multiple pancreatic lesions at 66Y. His first sister was diagnosed with CNS hemangioblastoma at 32Y, RCC at 36Y, and multiple pancreatic lesions at 36Y. His nephew and niece (son and daughter of first sister) of unknown ages are asymptomatic. His second sister was diagnosed with CNS hemangioblastoma at 39Y, RCC at 39Y, and multiple pancreatic lesions at 39Y. His nephew (son of second sister) of unknown age is asymptomatic. This cohort was also published in a paper by Wang et al., 2018 (PMID: 29330336). It is likely that both papers published the same family.
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www.ncbi.nlm.nih.gov www.ncbi.nlm.nih.gov
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www.sciencedirect.com www.sciencedirect.com
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Expression study of the new VHL isoforms in patients' cellsRNA sequencing (RNA-seq) analysis of patients' LCLs and tumors demonstrated that genomic variants in E1′ were associated with an upregulation of transcripts containing the E1′ cryptic exon compared with controls (Figure 3A; supplemental Figure 8). In addition, the mutated allele was preferentially expressed (>70%), suggesting a causal relationship between the genetic variants and E1′ retention (supplemental Figure 8C).Figure 3. Expression study of the new VHL transcript isoforms in patient cells. (A) Sashimi plots from RNA-seq data obtained from samples (LCLs or pheochromocytomas [Pheo]) of 3 patients from F8. The positions of the different VHL exons are indicated, with the maximal number of reads indicated at the right. Splice junctions are denoted by the horizontal links, with details provided in supplemental Figure 8. (B) TaqMan quantification of the different VHL isoforms from samples of F8 performed using probes specific to VHL E1-E2, the translated sequence upstream E1′, or E1-E1′ junctions. Relative gene expression was normalized to LCL control (C1) fixed at 1 (mean results of technical duplicates). (C) TaqMan quantification of the different VHL isoforms in LCLs (established from 2 independent controls and from patients of F1, F2, and F8) cultured in the absence or presence of puromycin (puro), an inhibitor of nonsense-mediated mRNA decay. TaqMan probes were specific to the VHL E1-E1′ or E1-E2 junction. The graph resumes experiments performed on LCLs cultured independently 3 times and quantified in duplicate. Data are represented as the mean ± standard error of the mean. (D) RT-PCR using primers specific for E1 and E3 was performed on mRNA extracted from LCLs established from controls and patients of F6 (carrying the mutation c.340+574A>T that targets the SA site of E1′). Patient with erythrocytosis is indicated in red. On the right, the spliced isoforms are schematically represented. **P < .05, ***P < .01 based on Student t test. *Denotes larger fragments that contained E1′ spliced with E1, but with 15 nucleotides deleted (represented in red) by the use of an alternative SA site (sequences of the cloned bands are detailed in supplemental Figure 10).Download : Download high-res image (230KB)Download : Download full-size imageFigure 3. Expression study of the new VHL transcript isoforms in patient cells. (A) Sashimi plots from RNA-seq data obtained from samples (LCLs or pheochromocytomas [Pheo]) of 3 patients from F8. The positions of the different VHL exons are indicated, with the maximal number of reads indicated at the right. Splice junctions are denoted by the horizontal links, with details provided in supplemental Figure 8. (B) TaqMan quantification of the different VHL isoforms from samples of F8 performed using probes specific to VHL E1-E2, the translated sequence upstream E1′, or E1-E1′ junctions. Relative gene expression was normalized to LCL control (C1) fixed at 1 (mean results of technical duplicates). (C) TaqMan quantification of the different VHL isoforms in LCLs (established from 2 independent controls and from patients of F1, F2, and F8) cultured in the absence or presence of puromycin (puro), an inhibitor of nonsense-mediated mRNA decay. TaqMan probes were specific to the VHL E1-E1′ or E1-E2 junction. The graph resumes experiments performed on LCLs cultured independently 3 times and quantified in duplicate. Data are represented as the mean ± standard error of the mean. (D) RT-PCR using primers specific for E1 and E3 was performed on mRNA extracted from LCLs established from controls and patients of F6 (carrying the mutation c.340+574A>T that targets the SA site of E1′). Patient with erythrocytosis is indicated in red. On the right, the spliced isoforms are schematically represented. **P < .05, ***P < .01 based on Student t test. *Denotes larger fragments that contained E1′ spliced with E1, but with 15 nucleotides deleted (represented in red) by the use of an alternative SA site (sequences of the cloned bands are detailed in supplemental Figure 10).We performed quantitative RT-PCR using TaqMan probes specific for the different splicing junctions or for the region upstream of E1′ (location of probes shown in Figure 1C), which showed a strong upregulation of a unique isoform containing E1′ spliced with E1 in LCLs and tumors from patients of F8 compared with controls (Figure 3B). The study therefore focused on the isoform E1-E1′. Transcripts that retained E1′ spliced with E1 contained (in-frame with E1) a premature termination codon (Figure 1C) and could likely be targeted for degradation according to nonsense-mediated mRNA decay (NMD) mechanisms. We therefore investigated the expression of transcripts that contained E1 spliced with E1′ in the absence or presence of puromycin, an inhibitor of NMD. Without puromycin, higher levels of expression were seen in samples with mutated E1′ (Figure 3C) compared with samples containing WT E1′. Exposure to puromycin resulted in a profound induction of isoforms containing E1 spliced with E1′ vs other isoforms (Figure 3C; supplemental Figure 9). These results indicated that isoforms with E1-E1′ junction were degraded by NMD and may have failed to produce proteins. We performed RT-PCR on LCL samples of F6 carrying the mutation in the SA site, using primers in VHL exons E1 and E3. We observed fragments of larger size in samples from patients carrying the mutation, which were highly visible in the presence of puromycin (Figure 3D). Cloning and sequencing of these fragments demonstrated a dysregulated splicing of E1′ with the use of an alternative SA site located 15 nucleotides downstream (supplemental Figure 10).To measure the impact of the splicing dysregulation on pVHL expression, we performed an immunoblot with an antibody able to recognize the amino acids encoded by E1 and therefore able to detect the different pVHL isoforms.8 The antibody detected overexpressed exogenous X1 protein after transfection of the plasmid encoding X1 (Figure 4A). However, it failed to detect the endogenous protein, even in patients' samples that overexpressed the mRNA containing E1-E1′. Instead, the immunoblots showed a lower expression of all the VHL protein isoforms in patients with mutated E1′ (Figures 4A-B).Figure 4. Functional studies of mutations in VHL E1′. (A-B) Immunoblot analysis of patient LCLs. A representative immunoblot (A) and quantification of 3 different immunoblots (B) are presented. Relative gene expression was normalized to glyceraldehyde-3-phosphate dehydrogenase (GAPDH) expression, and results obtained with LCL control (C1) were fixed at 100%. Data are represented as the mean ± standard error of the mean. A VHL antibody that recognized VHL E1 was able to detect the hypothetical X1 protein. In the most left lane, control LCLs were transfected with an expression vector containing the coding sequence for X1; 5 µg of proteins were blotted vs 45 µg for other samples to avoid signal saturation with overexpressed X1. Patients with erythrocytosis are indicated in red. (C) Functional hypoxia response element (HRE)–dependent reporter assays were performed in 786-O cells (ie, VHL− cells that constitutively express HIF-2α). The results are expressed as relative firefly luciferase activity with Renilla luciferase as an internal control; 1.0 unit denotes the basal activity of endogenous HIF-2α using the HRE luciferase reporter plasmid. The ability of WT and mutated X1 to downregulate firefly luciferase activity (related to HIF activity) was compared with pVHL and in competition with pVHL. An immunoblot using an antibody specific to the hemagglutinin tag (HA) was used to detect HA-VHL and HA-X1. X1-L128V+L138P corresponds to a potential impact of the c.340+648T>C and c.340+617C>G mutations on the hypothetical X1 protein. Three independent experiments were performed. (D) Characterization of VHL E1′ retention by the minigene experiment (representative picture of agarose gel; n = 3). RT-PCR was performed on mRNA obtained from cell lines transfected with a minigene construct containing VHL E1′ (WT or mutated) flanked by large intronic sequences cloned between the SERPING1 exons (exons A and B, targeted by the RT-PCR primers). The plasmids were transfected, and the expression of the spliced chimeric transcripts (containing EA and EB ± E1′) was analyzed. Two WT constructs containing E1′ were used; 1 contained the single-nucleotide polymorphism c.340+1150T>C (rs779808). Bands corresponding to EA and EB spliced together or with VHL E1′ are indicated on the right. *P < .05, **P < .01, ***P < .001, ****P < .0001 based on Student t test. †Corresponds to unspecific bands verified by sequencing. The minigene experiment performed with the construction carrying the mutation c.340+574A>T (that targets the SA site of E1′ in F6) confirmed the use of an alternative SA site (right panel) with the deletion of 15 nucleotides (represented in red). ns, not significant.Download : Download high-res image (204KB)Download : Download full-size imageFigure 4. Functional studies of mutations in VHL E1′. (A-B) Immunoblot analysis of patient LCLs. A representative immunoblot (A) and quantification of 3 different immunoblots (B) are presented. Relative gene expression was normalized to glyceraldehyde-3-phosphate dehydrogenase (GAPDH) expression, and results obtained with LCL control (C1) were fixed at 100%. Data are represented as the mean ± standard error of the mean. A VHL antibody that recognized VHL E1 was able to detect the hypothetical X1 protein. In the most left lane, control LCLs were transfected with an expression vector containing the coding sequence for X1; 5 µg of proteins were blotted vs 45 µg for other samples to avoid signal saturation with overexpressed X1. Patients with erythrocytosis are indicated in red. (C) Functional hypoxia response element (HRE)–dependent reporter assays were performed in 786-O cells (ie, VHL− cells that constitutively express HIF-2α). The results are expressed as relative firefly luciferase activity with Renilla luciferase as an internal control; 1.0 unit denotes the basal activity of endogenous HIF-2α using the HRE luciferase reporter plasmid. The ability of WT and mutated X1 to downregulate firefly luciferase activity (related to HIF activity) was compared with pVHL and in competition with pVHL. An immunoblot using an antibody specific to the hemagglutinin tag (HA) was used to detect HA-VHL and HA-X1. X1-L128V+L138P corresponds to a potential impact of the c.340+648T>C and c.340+617C>G mutations on the hypothetical X1 protein. Three independent experiments were performed. (D) Characterization of VHL E1′ retention by the minigene experiment (representative picture of agarose gel; n = 3). RT-PCR was performed on mRNA obtained from cell lines transfected with a minigene construct containing VHL E1′ (WT or mutated) flanked by large intronic sequences cloned between the SERPING1 exons (exons A and B, targeted by the RT-PCR primers). The plasmids were transfected, and the expression of the spliced chimeric transcripts (containing EA and EB ± E1′) was analyzed. Two WT constructs containing E1′ were used; 1 contained the single-nucleotide polymorphism c.340+1150T>C (rs779808). Bands corresponding to EA and EB spliced together or with VHL E1′ are indicated on the right. *P < .05, **P < .01, ***P < .001, ****P < .0001 based on Student t test. †Corresponds to unspecific bands verified by sequencing. The minigene experiment performed with the construction carrying the mutation c.340+574A>T (that targets the SA site of E1′ in F6) confirmed the use of an alternative SA site (right panel) with the deletion of 15 nucleotides (represented in red). ns, not significant.Functional characterization of the mutated VHL E1′Because the hypoxia pathway represents the major pathway involved in the genesis of secondary erythrocytosis and VHL disease,13, 14, 1528 we performed functional studies of the hypothetical WT or mutated X1 proteins using hypoxia response element–dependent reporter assays. These functional tests failed to reveal any substantial effects of X1 on this pathway, either alone or in competition with pVHL (Figure 4C; supplemental Figure 11). We next focused our study on a potential impact of the E1′ variants on splicing by performing splicing reporter minigene assays in various cell lines. The experiments showed that splicing of WT E1′ was barely detected (Figure 4D). Interestingly, higher molecular weight bands corresponding to the expected spliced isoforms containing E1′ appeared in the presence of the mutations. Cloning and sequencing of the isoforms confirmed a retention of E1′ at the expected splicing sites. The level of expression of this upper isoform, specific to E1′ inclusion, was higher for mutations associated with cancers than for those with erythrocytosis, independently of the cell lines. Notably, the combination of both variants associated with cancer had a more pronounced effect than each variant individually (the single-nucleotide polymorphism showing very low effect), suggesting a synergistic effect of the variants on splicing (supplemental Figure 12). In silico analysis of c.340+617C>G consistently predicted a severe alteration of splicing by the creation of an exonic splicing enhancer site (supplemental Figure 13).The minigene experiment performed with mutated E1′ at the SA site (F6) confirmed the inclusion of E1′ during splicing (Figure 4D, right panel), using the same downstream alternative SA site identified in mRNA extracted from patients' LCLs (supplemental Figure 10).Synonymous mutations in VHL E2 induce exon skippingWe then focused our study on the synonymous heterozygous D143D mutation in E2, identified in the proband of F1. This mutation was also identified in the homozygous state in 2 patients with erythrocytosis (F9 and F10; Figure 5A; Table 1). The mRNA extracted from LCLs established from the different members of these 2 families was reverse transcribed and sequenced. Comparison of chromatograms obtained by sequencing of DNA vs cDNA displayed a weaker peak of the mutated allele in cDNA, reflecting a decreased expression of the mRNA transcripts carrying the mutation.Download : Download high-res image (221KB)Download : Download full-size imageFigure 5. Genetic and expression study of synonymous mutations in VHL E2. (A-B) Pedigree and sequence chromatograms of germline DNA, tumor (pheochromocytoma) DNA, or cDNA prepared from 2 families (F9 and F10) with erythrocytosis (A) and 2 families (F11 and F12) with VHL disease (B). (C) Results of RT-PCR using mRNA extracted from LCLs (F9 and F10) and leukocytes and tumor material (pheochromocytoma) (F11 and F12). (D) TaqMan quantification of the different VHL isoforms in LCLs (established from patients of F9, F10, and F11) cultured in the absence or presence of puromycin. TaqMan probes are specific to the VHL E1-E2 or E1-E3 junction. Relative gene expression was normalized to LCL control (C1). (E) Immunoblot analysis of patient LCLs. Patients with erythrocytosis are indicated in red. A representative immunoblot (upper panel) and quantification of 4 different immunoblots are displayed (lower panel). Relative gene expression was normalized to glyceraldehyde-3-phosphate dehydrogenase (GAPDH) expression, and results obtained with C1 were fixed at 100%. Data are represented as the mean ± standard error of the mean. *P < .05, **P < .01, ***P < .001, ****P < .0001 based on Student t test. CNS, central nervous system.A different synonymous mutation in E2, c.414A>G p.Pro138Pro (P138P), was identified in 2 families (F11 and F12) with VHL disease (Figure 5B). This heterozygous mutation segregated with the disease in 3 generations. Sequencing of DNA extracted from the pheochromocytoma of F11-III.1 showed a loss of the WT allele in the tumor, demonstrating loss of heterozygosity as currently described in classical VHL disease.Suspecting an effect of the synonymous mutations on splicing, we next assessed the expression of the VHL transcripts in patients' samples by RT-PCR (Figure 5C). We found a significant change in the ratio of expressed VHL isoforms, with a higher expression of the E1-E3 transcripts in LCLs of patients homozygous for D143D and in the pheochromocytoma with P138P mutation. These results suggest an effect of the mutation on splicing regulatory elements, leading to E2 skipping. In silico analysis of the synonymous mutations indicated a potential effect on exonic splicing enhancer motifs (supplemental Figure 14).To specifically quantify the different VHL isoforms, we performed quantitative RT-PCR on LCLs using TaqMan probes complementary to the VHL E1-E2 or E1-E3 junction (Figure 5D). All mutated samples displayed an increase of the isoform with skipped E2 (E1-E3). The patients carrying a homozygous D143D mutation presented a severe decrease of the WT isoform expression level. These results demonstrated that synonymous mutations in E2 affected mRNA isoform production.To evaluate a potential impact on protein expression, we performed a western blot analysis. We did not observe any overexpression of the pVHL172 isoform as expected from mRNA quantification studies. However, in patients homozygous for D143D, we detected a strong downregulation of all the pVHL isoforms, which was also observed to a lesser extent in LCL samples from heterozygous patients (Figure 5E).Proportion of VHL E2 skipping is correlated with disease severity in minigene experimentsTo study the impact of the synonymous E2 mutations on splicing in different cell lines, we performed minigene assays. We tested the implications of the D143D and P138P mutations on splicing in addition to the nearby mutations described in patients with erythrocytosis (P138L and G144R).4,6,29 Indeed, these mutations may also affect splicing rather than VHL protein function. We first evaluated the loss of function of these mutants by reporter assays. We found that these could downregulate HIF in a manner similar to the WT protein, in contrast to VHL proteins lacking E2 (pVHLΔE2), which are described as nonfunctional in terms of their regulation of HIF activity8, 9, 1012 (Figure 6A). Minigene experiments were performed in a variety of cell lines relevant to the studied diseases, using LCLs as control (Figure 6B). We demonstrated that all mutations caused E2 skipping in LCLs. In other cell lines, these experiments demonstrated a major impact on the VHL E2 splicing of the P138P mutation, which is associated with cancer. The mutations P138L, D143D, and G144R, which are all associated with erythrocytosis, displayed a weaker effect on splicing, with slight variations among cell lines but with a stronger effect in the erythroid cell line (UT7 cultured with erythropoietin).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).Download : Download high-res image (254KB)Download : Download full-size imageFigure 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).Splicing dysregulation of VHL is causal in the development of diseaseRNA-seq confirmed that the synonymous mutations were not silent but instead induced potent E2 skipping (Figure 6C; supplemental Figure 15A). Additional transcriptome analyses of the pheochromocytoma carrying P138P showed an upregulation of HIF target genes (typically seen in VHL-related pheochromocytomas) compared with the pheochromocytoma carrying a RET mutation (supplemental Figure 15B).30 We then reanalyzed our independent cohort of pheochromocytomas30 using RNA-seq data from both tumors. After unsupervised classification, we observed a segregation of the P138P pheochromocytoma with other VHL-related tumors (C1B cluster), whereas the control pheochromocytoma bearing the RET mutation was grouped with other RET-related tumors (Figure 6D).
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iovs.arvojournals.org iovs.arvojournals.org
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486C→G Tv Exon 3 162 TGC C C162W
A study of 103 patients with VHL retinal manifestations and 108 patients without VHL retinal manifestations extracted from the French VHL database revealed that the number of hemangioblastomas appeared higher in patients who had a substitution when compared with patients with a truncated protein. Detected by PCR and SSCP, this mutation p.C162W (c.486C>G) was found in 4 VHL patients. All 4 didn’t have retinal hemangioblastomas, while other manifestations are not clearly stated. No family information or relation was provided. This is possibly previously published in PMID: 15300849
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345C→G Tv Exon 2 115 CAC H H115Q
A study of 103 patients with VHL retinal manifestations and 108 patients without VHL retinal manifestations extracted from the French VHL database revealed that the number of hemangioblastomas appeared higher in patients who had a substitution when compared with patients with a truncated protein. Detected by PCR and SSCP, this missense mutation (p.H115Q (c.345C>G)) was found in a VHL patient without retinal hemangioblastomas. Other manifestations are not clearly stated. No family information was provided. This is possibly previously published in PMID: 15300849
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pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov
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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.S65P (c.193T>C) germline variant of the VHL gene was detected in a family (ID 185). Member 9359 has unknown renal involvement. Member 9357 presented with mild renal disease. Member 1052 had no renal involvement. Member 3979 has moderate renal disease (RCC). The paper states that this family is previously reported in PMID 12202531, where 2 patients with this mutation are reported but relation between patients is unknown.
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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.C162Y (c.485G>A) germline variant of the VHL gene was detected in a family (ID 17). Member 753 presented with moderate renal disease (RCC), member 11338 had unknown renal involvement, member 696 presented with severe renal disease (RCC) and members 2368 and 699 presented with mild renal disease.
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www-sciencedirect-com.proxy1.lib.uwo.ca www-sciencedirect-com.proxy1.lib.uwo.ca
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nt 491 G to A, Gly to Asp
Fourty-four of 389 patients with VHL (between 1988-1999) screened positive for PNETs either by pathologic analysis of tissue specimens or by characteristic radiographic appearance on CT and MRI. VHL gene germline mutations were determined by quantitative Southern blotting to detect deletions of the gene and gene rearrangements as well as complete gene sequencing. One patient (20), a 68-year-old male, was found to harbour the c.278G>A mutation in the VHL gene (stated as 491 G to A in the paper which used the Latif sequence as reference) leading to an amino acid change of Gly to Asp at protein position 93. He presented with a single radiologic pancreatic neuroendocrine tumor. ACMG evidence codes: 'PP4' since the patient presents phenotypes highly specific for a disease with a single genetic etiology.
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2438Fnt 594, 595 GC to TT, Leu to PheP, 13775
PatientID: 24
KindredID: 3775
Case: F, 39Y3M, Ethnicity Unknown
DiseaseAssertion: VHL
FamilyInfo: N/A
CasePresentingHPOs: HP:0030405 (pancreatic endocrine tumour)
CaseHPOFreeText: She presented with 1 radiographic pancreatic neuroendocrine tumor diagnosed at age 38Y. Follow up 15M after EN surgery, currently no evidence of disease.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: N/A
Variant: p.L128F (c.381_382delinsTT)
LegacyVariant: p.L>F (c.594_595GC>TT)
CaseProblemVariantFreeText: N/A
ClinVarID: 223203 https://www.ncbi.nlm.nih.gov/clinvar/variation/223203
CAID: N/A
gnomAD: N/A
VariantEvidence: N/A
MutationType: delins
CivicName: L128F (c.381_382delinsTT)
MultipleGeneVariants: N/A
Tags
- Mutation:Germline
- cDNAposition:382
- ClinVarID:496054
- ProteinPosition:128
- CivicName:L128F(c.381_382delinsTT)
- InheritancePattern:AutosomalDominant
- AgeOfPresentation:pancreaticendocrinetumor:38
- VHL Hypothesis Annotation
- EvidenceStatement
- MutationType:delins
- DiseaseEntity:pancreaticendocrinetumor
- ClinVarID:Yes
- AminoAcidChange:LEUtoPHE
- AssumedRefSeq:AF010238.1
- DiseaseEntity:VHL
- ClinVarID:223203
- inferred_gene_hgnc:12687
- cDNAposition:381
- NoFamilyInfo
- inferred_gene_source:ClinVar
Annotators
URL
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pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov
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Through PCR purification and Sanger sequencing of peripheral blood (using an alcohol precipitation method), 121 consecutive, unrelated, index PCC/PGL patients underwent genetic testing for five PCC/PGL susceptibility genes (RET, VHL, SDHB, SDHD and SDHC) and were evaluated for clinical diagnosis of neurofibromatosis type1. A 15 year old male was genetically confirmed with a familial mutation at c.293A>C of the VHL gene. He presented with a sympathetic paraganglioma at age 12, and unilateral pheochromocytoma and retinal angioma (likely age 15). Further family history is unknown.
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nyaspubs-onlinelibrary-wiley-com.proxy1.lib.uwo.ca nyaspubs-onlinelibrary-wiley-com.proxy1.lib.uwo.ca
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R167W.
The aim of this study was to establish the characteristics of pheochromocytoma in a population of 58 patients between 4 and 20 years of age studied at Hospital de Niños Ricardo Gutiérrez. They represented a 23% of the total population of 255 pheochromocytoma patients studied. Two children belonging to the same family had VHL type 2A and presented with the missense mutation Arg167Trp. The children both had pheochromocytomas.
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journals-lww-com.uhn.idm.oclc.org journals-lww-com.uhn.idm.oclc.org
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The ELST shown in Figure 1 occurred in the left temporal bone of an 8-year-old boy who presented with profound sensorineural hearing loss, intermittent vertigo, and vHL based on mutation analysis that showed a G-to-C nucleotide 601 mutation in the vHL gene on chromosome 3. High-resolution computed tomographic imaging using a bone-window protocol demonstrates a destructive mass involving the posterior aspect of the left petrous temporal bone centered midway between the internal auditory canal and the sigmoid sinus. Bony erosion extends into the posterior semicircular canal, and there are areas of stippling and central calcification within the mass suggestive of an aggressive, erosive process. Magnetic resonance images of ELSTs may demonstrate enhancement on precontrast T1-weighted images and heterogeneous enhancement on T2-weighted images. Larger lesions may show flow voids. Although the diagnosis in this case was relatively straightforward on the basis of the combination of genetic screening studies and characteristic imaging features on computed tomographic scanning, a differential diagnosis of similar lesions should include meningioma, choroid plexus papilloma, paraganglioma, chondrosarcoma, and metastasis.
This paper shows the imaging result of an endolymphatic sac tumor found in the left temporal bone of an 8-year-old boy who presented with profound sensorineural hearing gloss, intermittent vertigo. VHL mutation analysis showed c.388G>C mutation (noted as G-to-C nucleotide 601 mutation in the paper).
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onlinelibrary.wiley.com onlinelibrary.wiley.com
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c.269A > T p.Asn90Ile
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 the c.269A>T (p.N90I) mutation. This member presented with retinal hemangiomas. No family information was provided.
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pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov
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pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov
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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 (S111R (c.333C>G)) was taken from the National Cancer Institute database, with an unknown number of members belonging to Family ID 4401NCI. It was reported in the paper as c.546C>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.
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Germline mutations were identified in 300/469 (63%) of the families tested; 137 distinct intragenic germline mutations were detected.
GroupID/ KindredID: 45CE
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 Munich, university of Freiburg and Institute of Pathology database, with an unknown number of members belonging to Family ID 45CE. 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: (c.463+1G>C)
LegacyVariant: Splice (c.676+1G>C)
CaseProblemVariantFreeText: N/A
ClinVarID: 223217 https://www.ncbi.nlm.nih.gov/clinvar/variation/223217
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: splice_site_variant
CivicName: Splice Site (c.463+1G>C)
MultipleGeneVariants: N/A
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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 (F136C (c.407T>G)) was taken from the Bristol Myers Squibb database, with an unknown number of members belonging to Family ID 10BMS. It was reported in the paper as c.620T>G 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.
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Germline mutations were identified in 300/469 (63%) of the families tested; 137 distinct intragenic germline mutations were detected.
GroupID/ KindredID: 28BMS
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 28BMS. 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: (c.464-2A>G)
LegacyVariant: Splice (c.677-2A>G)
CaseProblemVariantFreeText: N/A
ClinVarID: 223222 https://www.ncbi.nlm.nih.gov/clinvar/variation/223222/
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: splice_site_variant
CivicName: Splice Site (c.464-2A>G)
MultipleGeneVariants: N/A
Tags
- Mutation:Germline
- RefSeq:AF010238.1
- ClinVarID:223222
- ClinVarID:223217
- DiseaseEntity:renalcellcarcinoma
- InheritancePattern:AutosomalDominant
- VHL Hypothesis Annotation
- cDNAposition:464
- cDNAposition:463
- EvidenceStatement
- ClinVarID:223187
- ClinVarID:496065
- CivicName:SpliceSite(c.463+1G>C)
- Familial
- ClinVarID:Yes
- MutationType:splice_site_variant
- DiseaseEntity:VHL
- CivicName:SpliceSite(c.464-2A>G)
- inferred_gene_hgnc:12687
- inferred_gene_source:ClinVar
- FamilyCohort
Annotators
URL
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pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov
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GroupID: 78
DiseaseAssertion: VHL
GroupSize: N/A
GroupNumberMales: N/A
GroupNumberFemales: N/A
GroupEthnicity: N/A
GroupAgeRange: N/A
GroupInfo: VHL family found to have a germline rearrangement of the VHL gene. The number of family members included in this study is not specified.
GroupPresentingHPOs: N/A
GroupHPOFreeText: Patients within this family were found to have a clinical diagnosis of VHL disease, however, the presenting phenotypes were not specified.
GroupNotHPOs: HP:0002666 (Pheochromocytoma)
GroupNotHPOFreeText: N/A
GroupPreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: N/A
Variant: p.E186* (c.556G>T)
LegacyVariant: c.769G>T
CaseProblemVariantFreeText: N/A
ClinVarID: 381602, https://www.ncbi.nlm.nih.gov/clinvar/variation/381602/
CAID: N/A
gnomAD: N/A
VariantEvidence: N/A
MutationType: missense_variant;transversion
CivicName: E186* (c.556G>T)
MultipleGeneVariants: N/A
Tags
- Mutation:Germline
- RefSeq:AF010238.1
- ProteinPosition:186
- InheritancePattern:AutosomalDominant
- VHL Hypothesis Annotation
- MutationType:missense_variant;transversion
- Familial
- ClinVarID:Yes
- CivicName:E186*(c.556G>T)
- AminoAcidChange:GLUtoTER
- ClinVarID:381602
- DiseaseEntity:VHL
- inferred_gene_hgnc:12687
- inferred_gene_source:ClinVar
- FamilyCohort
- cDNAposition:556
Annotators
URL
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www.ncbi.nlm.nih.gov www.ncbi.nlm.nih.gov
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VHL: c.374A>C, p.His125Pro
A cohort of 64 pheochromocytoma and paragangliomas were screened for a BRAF mutation using direct Sanger sequencing and QRT-PCR. Genomic DNA was extracted from fresh or frozen peripheral blood. Germline mutations of VHL, SDHB, SDHD, and RET genes were also observed. The VHL mutation c.374A>C (p.His125Pro) was reported in patient #42, a 24Y male with bilateral pheochromocytoma. No family history was reported here.
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pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov
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PMID: 21461997
4 paediatric patients presenting with pheochromocytomas and paragangliomas were reported. Upon genetic testing of peripheral blood leukocytes on the VHL, SDHB, SDHC, SDHC, and RET genes, 1 patient was found to have the c.374A>C germline mutation. At 13Y the patient had bilateral adrenal pheochromocytoma and retinal capillary hemangiomas. Now, 19Y, he remains in complete remission. Family screening showed the absence of the mutation in the asymptomatic mother; the father was not analyzed. Other family history was negative for VHL syndrome and PCCs.
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onlinelibrary.wiley.com onlinelibrary.wiley.com
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PatientID: 6
KindredID: III
Case: Sex Unknown, Age Unknown, Chinese
DiseaseAssertion: VHL
FamilyInfo: Patient had three other family members with additional CNS hemangioblastomas and the same splice site mutation. Their one family member, patient 4, also presented with pancreatic tumors.
CasePresentingHPOs: HP:0010797 (hemangioblastoma)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: N/A
Variant: c.340+5G>C
LegacyVariant: c.553+5G>C
CaseProblemVariantFreeText: N/A
ClinVarID: 36901, https://www.ncbi.nlm.nih.gov/clinvar/variation/36901/
CAID: N/A
gnomAD: 0.01119 https://gnomad.broadinstitute.org/variant/3-10183876-G-C
VariantEvidence: This variant’s large allele frequency means this is likely non disease causing (not deleterious). Mutation was predicted to compromise the elongin-binding region. Refer to table 3 for LOH information on VHL and ZAC1.
MutationType: splice_site_variant
CivicName: Splice Region (c.340+5G>C)
MultipleGeneVariants: N/A
Tags
- cDNAposition:340
- Familial
- Mutation:Germline
- ClinVarID:Yes
- Ethnicity:Chinese
- MutationType:splice_site_variant
- AssumedRefSeq:AF010238.1
- CivicName:SpliceRegion(c.340+5G>C)
- DiseaseEntity:VHL
- InheritancePattern:AutosomalDominant
- inferred_gene_hgnc:12687
- VHL Hypothesis Annotation
- inferred_gene_source:ClinVar
- ClinVarID:36901
- DiseaseEntity:hemangioblastoma
Annotators
URL
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pubmed-ncbi-nlm-nih-gov.proxy1.lib.uwo.ca pubmed-ncbi-nlm-nih-gov.proxy1.lib.uwo.ca
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Screening of 92 unrelated patients with VHL disease revealed 61 DNA variants. No variants were found in 96 control cases. The V166F (c.496G>T) germline missense mutation was found in a VHL type 2A (with pheochromocytoma) patient (patient no. V49). This variant was not found in 8 unaffected family members and previously reported in patients with VHL. This patient was stated to be previously published in PMID 15300849.
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Screening of 92 unrelated patients with VHL disease revealed 61 DNA variants. Blood samples were isolated and sequenced by direct sequencing using prism-ready reaction dye primer cycle sequencing kits (Applied Biosystem Roissy CDG France) and an ABI 373A automated sequencer (AppliedBiosystem Roissy CDG France).No variants were found in 96 control cases. This stop gain mutation, c.481C>T, was found in 2 unrelated VHL type 1 patients (patient V3, V46). No patient information was provided and no additional family members were screened. Patient V3 was previously published in 8956040.
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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 F136S (c.407T>C) missense mutation was found in two unrelated VHL type 1 (no pheochromocytoma) patients (patient no. V53, V94). No unaffected individuals from either family were tested for this mutation.
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jnnp.bmj.com jnnp.bmj.com
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nt 676 +1 G/C Splice defect 676 +1 G/C Splice defect 2
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 splice site mutation (c.463+1G>C) was recorded in the paper as c.676+1G>C due to a difference in transcript sequence. It was found in 2 patients with hemangioblastomas of the central nervous system. Any family information or relations is unknown. No other phenotypes described.
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nt 407 C/G 65 Ser→Trp S65W Missense 2
GroupID: 2
DiseaseAssertion: hemangioblastoma
GroupSize: 2
GroupNumberMales: N/A
GroupNumberFemales: N/A
GroupEthnicity: N/A
GroupAgeRange: N/A
GroupInfo: 2 out of the 81 patients listed in this hemangioblastoma cohort were found with this c.194C>G mutation. Any relation is unknown.
GroupPresentingHPOs: HP:0010797 (hemangioblastoma)
GroupHPOFreeText: all patients had hemangioblastoma of the CNS; other phenotypes are unknown
GroupNotHPOs: N/A
GroupNotHPOFreeText: N/A
GroupPreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: N/A
Variant: p.S65W (c.194C>G)
LegacyVariant: p.S65W (c.407C>G)
CaseProblemVariantFreeText: N/A
ClinVarID: 43597 https://www.ncbi.nlm.nih.gov/clinvar/variation/43597/
CAID: N/A
gnomAD: N/A
VariantEvidence: N/A
MutationType: missense_variant;transversion
CivicName: S65W (c.194C>G)
MultipleGeneVariants: N/A
Tags
- Mutation:Germline
- ClinVarID:223217
- AminoAcidChange:SERtoTRP
- CivicName:S65W(c.194C>G)
- VHL Hypothesis Annotation
- ProteinPosition:65
- EvidenceStatement
- DiseaseEntity:hemangioblastoma
- ClinVarID:Yes
- AssumedRefSeq:AF010238.1
- ClinVarID:43597
- inferred_gene_hgnc:12687
- NoFamilyInfo
- MutationType:missense_variant;transition
- inferred_gene_source:ClinVar
- cDNAposition:194
Annotators
URL
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pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov
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PMID: 7977367
KindredID: 9
DiseaseAssertion: VHL
GroupSize: Unknown
GroupNumberMales: N/A
GroupNumberFemales: N/A
GroupEthnicity: N/A
GroupAgeRange: N/A
GroupInfo: This is a family belonging to prefigure No. 9. They are described as ‘VHL-affected’.
GroupPresentingHPOs: HP:0005584 (renal cell carcinoma)
GroupHPOFreeText: RCC-affected; other manifestations are possible but not clear.
GroupNotHPOs: N/A
GroupNotHPOFreeText: N/A
GroupPreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: N/A
Variant: p.Q145Hfs*28 (c.435_436delGC)
LegacyVariant: p.215fs (c.648_649delGC)
CaseProblemVariantFreeText: N/A
ClinVarID: 223210 https://www.ncbi.nlm.nih.gov/clinvar/variation/223210/
CAID: N/A
gnomAD: N/A
VariantEvidence: N/A
MutationType: minus_2_frameshift_variant
CivicName: Q145fs (c.435_436delGC)
MultipleGeneVariants: N/A
Tags
- ProteinPosition:145
- Mutation:Germline
- RefSeq:AF010238.1
- CivicName:Q145fs(c.435_436delGC)
- DiseaseEntity:renalcellcarcinoma
- InheritancePattern:AutosomalDominant
- VHL Hypothesis Annotation
- AminoAcidChange:GLNtoHIS
- Familial
- ClinVarID:Yes
- cDNAposition:435
- cDNAposition:436
- ClinVarID:223210
- MutationType:minus_2_frameshift_variant
- DiseaseEntity:VHL
- inferred_gene_hgnc:12687
- inferred_gene_source:ClinVar
Annotators
URL
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pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov
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One hundred and sixteen unrelated VHL disease patients have been investigated by molecular genetic analysis. Twenty-two of these were previously shown to have germline deletions on Southern analysis, and in the present study the remaining 94 patients were screened for intragenic mutations via SSCP and heteroduplex analysis of 855 bp of the VHL coding sequence and 800 bp of the 3' UTR. An intragenic mutation was identified in 55 (59%) out of 94 patients without germline deletions on Southern analysis. In all patients with multiple affected family members the missense mutation segregated with the disease. Large deletions or intragenic mutations predicted to cause a truncated protein were found in 36 of 53 families without pheochromocytoma (VHL type 1) and 2 of 12 families with pheochromocytoma (VHL type 2). This study also investigated the frequency of different mutation classes between kindreds with and without pheochromocytoma. The c.337C>T (p.R113) stop-gain mutation (noted as c.550C>T (p.R184) in the paper due to a difference in reference transcript used) was found in at least one patient in 2 kindreds (families): kindred no. 30 and 136. Pheochromocytoma was not observed in any members of kindred no. 136 (implying the affected patient(s) had VHL disease type 1). No phenotypic information was reported for members of kindred no. 30. ACMG evidence codes: none.
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One hundred and sixteen unrelated VHL disease patients have been investigated by molecular genetic analysis. Twenty-two of these were previously shown to have germline deletions on Southern analysis, and in the present study the remaining 94 patients were screened for intragenic mutations via SSCP and heteroduplex analysis of 855 bp of the VHL coding sequence and 800 bp of the 3' UTR. An intragenic mutation was identified in 55 (59%) out of 94 patients without germline deletions on Southern analysis. In all patients with multiple affected family members the missense mutation segregated with the disease. Large deletions or intragenic mutations predicted to cause a truncated protein were found in 36 of 53 families without pheochromocytoma (VHL type 1) and 2 of 12 families with pheochromocytoma (VHL type 2). This study also investigated the frequency of different mutation classes between kindreds with and without pheochromocytoma. The p.Y98H (c.292T>C) variant (noted asp.Y169H (c.505T>C) in the paper due to a difference in reference transcript used) was found in at least one patient in kindred 22. No familial phenotypic information could be inferred from the paper.
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onlinelibrary.wiley.com onlinelibrary.wiley.com
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Thirty-five unrelated patients suspected of having von Hippel-Lindau disease were analyzed and 32 VHL gene variants were found in 35 patients using PCR and SSCP by peripheral blood leukocytes. An association of clear cell renal carcinoma development with a relatively high loss of structural stability in VHL protein missense mutations was discovered. This missense variant (p.R167Q) was found in 4 patients (F8, F18, F56 and F71) all with retinal capillary hemangioma. Patient F8 was 35 years old at onset and noted of familial antecedents of phaeochromocytoma. Patient F18 was 33 years old at onset, had cerebellar hemangioblastoma, pancreatic cysts. Noted of familial antecedents of phaeochromocytoma and a total of 2 affected family members. Patient F56 was 45 years old at onset, had cerebellar hemangioblastoma and renal cyst. Also noted of familial antecedents of phaeochromocytoma and a total of 2 affected family members. Patient F71 was 25 years old at onset, had cerebellar hemangioblastoma, and unilateral pheochromocytoma. Noted a total of 2 affected family members, with the family member reported with clear cell renal cell carcinoma
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Thirty-five unrelated patients suspected of having von Hippel-Lindau disease were analyzed and 32 VHL gene variants were found in 35 patients using PCR and SSCP by peripheral blood leukocytes. An association of clear cell renal carcinoma development with a relatively high loss of structural stability in VHL protein missense mutations was discovered. This missense mutation (p.C162Y) was found in a patient, whose age of onset was 15 years old, with retinal hemangioblastomas, unilateral pheochromocytoma, and renal cysts (patient no. F61). Patient has family history of clear cell renal carcinoma.
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www.ncbi.nlm.nih.gov www.ncbi.nlm.nih.gov
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Case reportThe female patient, aged 49, reported pains in her second and third finger of the right hand that she had had for 2 years. Initial diagnosis revealed isthmus carpalis and the patient was operated on without much success—no improvement was noticed.A year later, intensifying root pains of Root C5 and C6 on the right side were the reason for performing an MRI scan of the cervical spine. The findings from the study showed an intramedullary lesion of 1.5 cm in diameter, localized at the height of C5–C6 with accompanying syrinx stretching from C3 to C7. The patient was consulted neurosurgically several times, but refused to submit to a surgical treatment. Gradually, the pains extended to the entire forearm of the upper right limb, and numbness appeared of both lower limbs. She met the clinical diagnostic criteria for VHL disease [11]. Sequencing of the VHL gene revealed the presence of the 393C>A (N131K) missense mutation (Fig. 1) [12]. VHL disease was also diagnosed in her relatives (shown in Fig. 2).
PatientID: III:2 (case)
KindredID: 1
Case: F, 49Y0M, Ethnicity Unknown
DiseaseAssertion: VHL
FamilyInfo: VHL disease was diagnosed in her relatives - although no genetic testing was directly performed on them prior to death. 2/3 of her siblings and her father were affected. Her father had retinal hemangioblastoma at 30Y, CNS hemangioblastoma at 40Y and died at 41Y. Her older brother had kidney cancer and died at 48Y, and her sister had retinal hemangioblastoma at 13Y and CNS hemangioblastoma at 29Y. The case’s daughter tested negative and their other living sister.
CasePresentingHPOs: HP:0009711; HP:0000107; HP:0009713; HP:0002668 (retinal capillary hemangioblastoma; renal cysts; spine hemangioblastoma; paraganglioma)
CaseHPOFreeText: patient at retinal hemangioblastoma at 22Y. At 47Y she reported pains in her second and third finger of the right hand. She developed large carotid body paraganglioma at the common carotid artery bifurcation, (49Y) coexisting with a hemangioblastoma situated intramedullary in region C5/C6 (the right-sided dorsal part of the spinal cord) at 47Y). 1 year after the hemangioblastoma resection, the spinal symptoms receded and the carotid body paraganglioma still was asymptomatic. Motor issues and Babinski syndrome were also observed.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: N/A
Variant: p.N131K (c.393C>A)
LegacyVariant: N/A
CaseProblemVariantFreeText: N/A
ClinVarID: 420074 https://www.ncbi.nlm.nih.gov/clinvar/variation/420074/
CAID: N/A
gnomAD: N/A
VariantEvidence: N/A
MutationType: missense_variant;transversion
CivicName: N131K (c.393C>A)
MultipleGeneVariants: N/A
Tags
- AgeOfPresentation:spinalhemangioblastoma:47
- ClinVarID:420074
- DiseaseEntity:retinalcapillaryhemangioma
- DiseaseEntity:paraganglioma
- InheritancePattern:AutosomalDominant
- VHL Hypothesis Annotation
- FamilyPedigree
- ProteinPosition:131
- AgeOfPresentation:paraganglioma:49
- MutationType:missense_variant;transversion
- AminoAcidChange:ASNtoLYS
- Familial
- CivicName:N131K(c.393C>A)
- ClinVarID:Yes
- DiseaseEntity:spinalhemangioblastoma
- AgeOfPresentation:retinalcapillaryhemangioma:22
- DiseaseEntity:VHL
- inferred_gene_hgnc:12687
- DiseaseEntity:renalcyst
- inferred_gene_source:ClinVar
- cDNAposition:393
Annotators
URL
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erc.bioscientifica.com erc.bioscientifica.com
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c.362 A>Gap.D121G
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. 2 patients were found to have the above mutation (c.362A>G). 1 was a VHL patient with an ICT (pancreatic neuroendocrine tumor) taken from the VHL-registry. The other patient was stated to be in this study with the given mutation, however no ICT. 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.
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www.ncbi.nlm.nih.gov www.ncbi.nlm.nih.gov
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VHLE2c.414A>Gp.P138P
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. Germline genetic testing revealed a synonymous P138P(c.414A>G) variant in exon 2 of the VHL gene, in 2 patients, 2 years after their diagnosis. Patient #86 is a male PPGL patient who first presented with bilateral pheochromocytoma at age 15 and was also diagnosed at age 15. They also have a family history of PPGL, which was not detailed further. Patient #87 is a male PPGL patient who first presented with pheochromocytoma at age 36 and was also diagnosed at age 36. Patient 87 does not have family history of PPGL.
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journals.lww.com journals.lww.com
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21 missense mutations, 5 nonsense 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 carcinoma in addition to pancreatic tumours. The presence of other phenotypes was not described. A missense mutation (c.334T>C) was found in 2 members of the same family. Patient No. 10 and patient no. 17 from family 360 both presented with pancreatic endocrine tumour. Their familial relation and other family members were not described therefore there may not be sufficient evidence for PP1. However, patients' phenotypes are highly specific to VHL disease (PP4) and disease-causing missense variants are common in VHL disease (PP2).
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pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov
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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 1
DiseaseAssertion: assumed VHL
GroupSize: 2
GroupNumberMales: N/A
GroupNumberFemales: N/A
GroupEthnicity: German
GroupAgeRange: N/A
FamilyInfo: 2 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 second patient had this precise mutation, although assumed.
GroupPresentingHPOs: HP:0009711; HP:0002666 (retinal capillary hemangioma, pheochromocytoma)
GroupHPOFreeText: both individuals had Pheos, whereas only 1 person had a retinal capillary hemangioma.
GroupNotHPOs: HP:0010797; HP:0005584; HP:0001737; HP:0009715 (hemangioblastoma, 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
Tags
- Mutation:Germline
- DiseaseEntity:pheochromocytoma
- DiseaseEntity:retinalcapillaryhemangioma
- ExperimentalAssay
- PreviouslyPublished
- InheritancePattern:AutosomalDominant
- VHL Hypothesis Annotation
- cDNAposition:292
- Familial
- ClinVarID:Yes
- CivicName:Y98H(c.292T>C)
- AssumedRefSeq:AF010238.1
- DiseaseEntity:VHL
- ProteinPosition:98
- inferred_gene_hgnc:12687
- MutationType:missense_variant;transition
- ClinVarID:2223
- AminoAcidChange:TYRtoHIS
- inferred_gene_source:ClinVar
- FamilyCohort
- Ethnicity:German
Annotators
URL
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academic.oup.com academic.oup.com
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709 G-->T transversion present in all affected subjects and in four presymptomatic children.
PatientID: II:7
KindredID: 1
Case: M, Age Unknown, Jewish
DiseaseAssertion: VHL
FamilyInfo: This kindred of Jewish-Kurdish origin consisted of 3 generations of 25 members. 7 were clinically affected subjects with pheochromocytoma (5 of which had the confirmed mutation - I:1, II:2, II:4, II:7 and II:9, as the other 2, II:5 and II:10 were said to have passed due to complications of the disease - prior to any genetic testing), and 4 others were carriers, or pre-symptomatic (III:1, III:3, III:7 and III:12). Subject 11:7 developed a cerebellar hemangioblastoma 25 yr after his initial diagnosis of pheochromocytoma, leading to the clinical diagnosis of VHL in the kindred.
CasePresentingHPOs: HP:0002666; HP:0006880; HP:0030074 (pheochromocytoma, cerebellar hemangiolastoma, chemodectoma)
CaseHPOFreeText: patient had cerebellar HB at 25Y, after his initial diagnosis with bilateral pheochromocytoma, and then also extra-adrenal chromafin tumors (carotid body chemodectoma).
CaseNotHPOs: HP:0005584 (renal cell carcinoma)
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: 33471715
SupplementalData: N/A
Variant: p.V166F (c.496G>T)
LegacyVariant: p.V166F (c.709G>T)
CaseProblemVariantFreeText: N/A
ClinVarID: 2224, https://www.ncbi.nlm.nih.gov/clinvar/variation/2224/
CAID: N/A
VariantEvidence: N/A
VariantEvidence: N/A
MutationType: missense_variant;transversion
CivicName: V166F (c.496G>T)
MultipleGeneVariants: N/A
Tags
- Mutation:Germline
- AminoAcidChange:VALtoPHE
- DiseaseEntity:pheochromocytoma
- DiseaseEntity:cerebellarhemangioblastoma
- cDNAposition:496
- ProteinPosition:166
- InheritancePattern:AutosomalDominant
- CivicName:V166F(c.496G>T)
- AgeOfPresentation:cerebellarhemangioblastoma:25
- VHL Hypothesis Annotation
- FamilyPedigree
- MutationType:missense_variant;transversion
- Familial
- ClinVarID:2224
- ClinVarID:Yes
- DiseaseEntity:chemodectoma
- AssumedRefSeq:AF010238.1
- DiseaseEntity:VHL
- inferred_gene_hgnc:12687
- inferred_gene_source:ClinVar
- Ethnicity:Jewish
Annotators
URL
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erc.bioscientifica.com erc.bioscientifica.com
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235 (CAG-TAG)1 (1)163HBr, HBc, HBsc, RCC, Cr
GroupID: None
Case: Sex Unknown, 63Y0M, Dutch
DiseaseAssertion: VHL
FamilyInfo: N/A
CasePresentingHPOs: HP:0009711, HP:0006880, HP:0009713, HP:0005584, HP:0000107 (Retinal capillary hemangioma, Cerebellar hemangioblastoma, Spinal hemangioblastoma, Renal cell carcinoma, Renal cyst)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: This cohort was published later in PMID 31087189
SupplementalData: N/A
Variant: p.R79C (c.235C>T)
LegacyVariant: c.235 (CAG-TAG)
CaseProblemVariantFreeText: written in the publication as c.235 (CAG-TAG), deduced to c.235C>T: p.Arg79Cys updated nomenclature
ClinVarID: 161400 https://www.ncbi.nlm.nih.gov/clinvar/variation/161400/
CAID: N/A
gnomAD: 0.00002168, https://gnomad.broadinstitute.org/variant/3-10183766-C-T
VariantEvidence: N/A
MutationType: missense_variant; transition
CivicName: R79C (c.235C>T)
MultipleGeneVariants: N/A
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c.241C>T
Data was collected from 82 VHL mutation carriers in the Dutch VHL surveillance program. Two patients were found with the missense mutation, c.241C>T, in the VHL gene. One patient was 34Y and the other was 59Y at last follow-up. Their phenotypes were grouped together: retinal hemangioblastoma, cerebellar hemangioblastoma, spinal cord hemangioblastoma, renal cell carcinoma, pancreatic neuroendocrine tumour, pheochromocytoma, and renal cysts. Family history was not described. The group was classified as a 2a/b which was described by the author to included de novo VHL mutation carriers or VHL mutation carriers having a family history with diagnosis of pheochromocytoma and other VHL related manifestations.
Tags
- Mutation:Germline
- DiseaseEntity:cerebellarhemangioblastoma
- ClinVarID:161400
- DiseaseEntity:retinalcapillaryhemangioma
- cDNAposition:235
- DiseaseEntity:renalcellcarcinoma
- InheritancePattern:AutosomalDominant
- ProteinPosition:79
- VHL Hypothesis Annotation
- EvidenceStatement
- CivicName:R79C(c.235C>T)
- AminoAcidChange:ARGtoCYS
- ClinVarID:Yes
- Ethnicity:Dutch
- ClinVarID:2233
- DiseaseEntity:spinalhemangioblastoma
- DiseaseEntity:VHL
- inferred_gene_hgnc:12687
- MutationType:missense_variant;transition
- NoFamilyInfo
- DiseaseEntity:renalcyst
- inferred_gene_source:ClinVar
Annotators
URL
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onlinelibrary.wiley.com onlinelibrary.wiley.com
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This study reports 1,548 germline and somatic mutations from 945 VHL families, including 30 previously unpublished kindreds from The Netherlands (six novel mutations). This mutation was detected by direct sequencing and MLPA. This frameshift mutation (c.351del) was detected as sporadic germline in case no. 198 with hemangioblastoma of the central nervous system. The case phenotypes are highly specific for a disease with a single genetic etiology (ACMG code: PP4).
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onlinelibrary-wiley-com.ezproxy.lib.ryerson.ca onlinelibrary-wiley-com.ezproxy.lib.ryerson.ca
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c.337C > T (p.Arg113X)
37 Danish patients diagnosed with VHL before 18 years from a prospective cohort study from Denmark's National vHL Research Database (Binderup et al., 2013) were assessed. Parts of the Danish cohort have been previously assesed in the following papers PMID: 19863552, 25834951, 27966541, 27539272. Peripheral blood samples were isolated and sequenced coding exons and exon-intron boundaries using MLPA (Multiplex Ligation-dependent Probe Amplification). One family with one patient (Family ID-10) was found with a germline truncating mutation in the VHL gene (R113*; c.337C>T). Patient 1 was diagnosed at 15Y and had two pancreatic cysts at 15Y, one retinal hemangioblastoma at 17Y, and one epididymal cystadenoma at 17Y. The patient was 37Y by the end of the study.
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www.ncbi.nlm.nih.gov www.ncbi.nlm.nih.gov
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14EP 1.0VVHLVHL({"type":"entrez-nucleotide","attrs":{"text":"NM_000551.4","term_id":"1779521775","term_text":"NM_000551.4"}}NM_000551.4):c.407T>G (p. Phe136Cys)
This study investigated the effectiveness of whole exome sequencing (WES) and an in-house hybridization based gene panel (ENDOGENE Panel v2.0) at detecting mutations in pheochromocytoma/paraganglioma (PPGL) related genes. The ENDOGENE panel included EGLN1, EPAS1, FH, KIF1B, MAX, MEN1, NF1, RET, SDHA, SDHB, SDHC, SDHD, SDHAF2, TMEM127, VHL, GOT2, MDH2 and SLC25A11. WES and the ENDOGENE panel were tested on 37 samples with known variants. After optimization of the bioinformatic pipeline, 61 additional samples were tested prospectively. VHL mutations were identified in 3 patients and all were confirmed by Sanger sequencing of blood. Patient 14 was found to have a F136C(c.407T>G) missense variant and diagnosed with VHL.
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www.ncbi.nlm.nih.gov www.ncbi.nlm.nih.gov
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8684 C->T substitution causing the nonsense R161X mutation
The proband (II/1), of Italian descent, was found to have the c.481C>T change (referred to in the paper as 8684 C->T due to a difference in transcript sequence) causing a p.R161* mutation in the VHL gene. This variant was detected using direct sequencing of PCR products obtained from genomic DNA extracted from the patients peripheral blood leukocytes using the DNA extractor BIO ROBOT EZ 1 (Qiagen). Genetic testing revealed that her parents did not have the VHL gene mutation. She presented with a cerebellar hemangioblastoma at age 33. ACMG evidence codes: 'PS2' since both parents are tested and do not present with the variant (de novo), 'PP4' since the patient presents phenotypes highly specific for a disease with a single genetic etiology.
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www.ncbi.nlm.nih.gov www.ncbi.nlm.nih.gov
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F4c.337C>T1p.Arg113TerNonsensePathogenicYesF5c.337C>T1p.Arg113TerNonsensePathogenicYes
17 patients from 10 families affected with VHL syndrome, particularly with retinal capillary hemangioblastomas (RCHs) were examined. In 2019, a 14-year-old boy (patient 8) from family 4 was diagnosed with visual impairment, due to visual acuity of 20/20 in the right eye and 20/640 in the left eye. Four peripheral RCHs were detected in the right eye. The visual impairment of the left eye was due to the severe exudative process involving the macula. Moreover, numerous microhemangioblastomas were revealed by fluorescein angiography. Laser therapy was performed in both eyes, but vitreous hemorrhage occurred in the left eye. Bevacizumab was given three times, as well simultaneous cryotherapies were performed under general anesthesia. Many laser sessions were performed for regression of the RCHs to occur. Further testing revealed a cerebellar hemangioblastoma. Genomic DNA was extracted from whole blood for sanger sequencing of the VHL gene and multiplex ligation-dependent probe amplification was performed to identify genomic rearrangements. A nonsense R113(c.337C>T) mutation was identified in exon1 of the VHL gene. The parents of patient 8 were molecularly tested and neither possessed the mutation; thus, the mutation was identified as de novo. Neither parent had VHL syndrome characterized by RCHs. A 32-year-old woman (patient 9) from family 5 had been diagnosed in 2000 with multiple cerebellar and spinal hemangioblastomas. In 2005, she was examined at the eye clinic, and were visual acuity was 20/20 and 20/25 in the right and left eye, respectively. No abnormalities were found in the right eye, but a peripheral RCH that was already partially treated with laser was observed in the left eye. Many tiny RCHs that surrounded the major lesion were also detected in this eye. Further laser treatments were scheduled, but the patient did not follow up and instead came to the ophthalmic emergency service three years later. Visual acuity of the left eye worsened to 20/640, and she presented with retinal detachment. The partially treated RCH of the left eye worsened and more tiny RCHs were detected. Cryotherapy was performed in the left eye but retinal detachment was still present at follow-up. On follow-up, no RCHs were detected in the right eye, and vision loss developed in both eyes. The same nonsense R113(c.337C>T) mutation was identified in exon1 of the VHL gene in this patient. Neither parent of patient 9 had VHL syndrome characterized by RCHs.
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www.ncbi.nlm.nih.gov www.ncbi.nlm.nih.gov
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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: IV-2
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 patient (IV-2) appears to have inherited this disease from her father, along with many of her siblings. She also had an affected daughter with retinal angiomas. See Fig. 1 for family pedigree.
CasePresentingHPOs: HP:0009711 (retinal capillary hemangioma)
CaseHPOFreeText: This member had retinal angiomas which was not further described.
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
Tags
- Mutation:Germline
- DiseaseEntity:retinalcapillaryhemangioma
- CivicName:R167W(c.499C>T)
- InheritancePattern:AutosomalDominant
- VHL Hypothesis Annotation
- FamilyPedigree
- AminoAcidChange:ARGtoTRP
- ClinVarID:2218
- Familial
- ClinVarID:Yes
- RefSeq:N/A
- inferred_gene_hgnc:12687
- ProteinPosition:167
- MutationType:missense_variant;transition
- inferred_gene_source:ClinVar
- cDNAposition:499
Annotators
URL
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link.springer.com link.springer.com
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GroupID/ KindredID: VHL 31
Case: Sex unknown, Age unknown, Italian
DiseaseAssertion: assumed VHL
FamilyInfo: One patient with the given mutation is stated to belong to VHL family 31 - this was said to be not inherited from either parent, indicating a de novo germline mutation.
CasePresentingHPOs: HP:0009711; HP:0010797; HP:0000107; HP:0005584; HP:0001737; HP:0009715 (retinal capillary hemangioma, hemangioblastoma, renal cyst, renal cell carcinoma, pancreatic cysts, papillary cystadenoma of the epididymis)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: N/A
Variant: c.464-2A>G
CaseProblemVariantFreeText: N/A
LegacyVariant: c.677-2A>G
ClinVarID: 223222 https://www.ncbi.nlm.nih.gov/clinvar/variation/223222/
CAID: N/A
gnomAD: N/A
VariantEvidence: N/A
MutationType: splice_site_variant
CivicName: Splice Site (c.464-2A>G)
MultipleGeneVariants: N/A
Tags
- Mutation:Germline
- RefSeq:AF010238.1
- ClinVarID:223222
- DiseaseEntity:retinalcapillaryhemangioma
- InheritancePattern:DeNovoAssertion
- deNovoConfirmed
- DiseaseEntity:renalcellcarcinoma
- VHL Hypothesis Annotation
- cDNAposition:464
- NonFamilial
- DiseaseEntity:hemangioblastoma
- DiseaseEntity:papillarycystadenomaoftheepididymis
- ClinVarID:Yes
- MutationType:splice_site_variant
- DiseaseEntity:VHL
- CivicName:SpliceSite(c.464-2A>G)
- DiseaseEntity:pancreaticcysts
- inferred_gene_hgnc:12687
- Ethnicity:Italian
- DiseaseEntity:renalcyst
- inferred_gene_source:ClinVar
Annotators
URL
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www.ncbi.nlm.nih.gov www.ncbi.nlm.nih.gov
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c.500G>A, p.(R167Q))
This paper analyzed 8 patients with clinical or imaging features consistent with VHL, but who tested negative for an abnormality by Sanger sequencing and deletion analysis. All eight patients were subsequently analyzed by next generation sequencing using peripheral blood lymphocytes. The missense mutation, c.500G>A, was found in Patient 1 in mosaic with a frequency of the mutated allele of 5.7%. This patient presented with CNS hemangioblastoma at the age of 16 and developed pheochromocytoma, pancreatic neuroendocrine tumour, and adrenal pheochromocytoma at the age of 17. The patient had no family history of VHL. This patient is believed to be the same as a patient published in 30731206. That paper offers more updated information on this patient.
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www.ncbi.nlm.nih.gov www.ncbi.nlm.nih.gov
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c.337C>Tp.Arg113X
Genomic DNA was extracted from whole blood samples for genetic testing of SDHB, SDHC, SDHD, and VHL. 27 patients with urinary bladder paragangliomas, revealed 17 germline mutations, three of which were in the VHL gene. PCR–based bidirectional sequencing was performed along with MLPA on large deletions. This nonsense mutation (p.R113*) was found in a 37-year-old female (patient no. 21). Family history of pheo or paragangliomas was said to be positive.
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pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov
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Patients: Two generations of a family consisting of 15 individuals were studied.
PatientID: III:9
KindredID: 1
Case: F, 25Y, Spanish
DiseaseAssertion: pheochromocytoma
FamilyInfo: Spanish family of 15 members studied, over 2 generations. 6 members had VHL presentations, 1 was a carrier, and 4 others had the mutation, while 2 were not sequenced. This patient’s sister was a carrier, while her mother mother, uncle, and cousins were affected.
CasePresentingHPOs: HP:0002666 (pheochromocytoma)
CaseHPOFreeText: First studied at 19Y, she had a bilateral tumor accumulation (Right, 6cm and Left 4cm).
CaseNotHPOs: HP:0006880; HP:0009711 (cerebellar hemangioblastoma, retinal capillary hemangioma)
CaseNotHPOFreeText: Brain MRI and CT-scans were normal, and no signs of retinal angiomas were present.
CasePreviousTesting: RET
PreviouslyPublished: N/A
SupplementalData: N/A
Variant: p.R167W (c.499C>T)
LegacyVariant: p.R238T, C>T
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
VariantEvidence: N/A
MutationType: missense_variant;transition
CivicName: R167W (c.499C>T)
MultipleGeneVariants: N/A
Tags
- Mutation:Germline
- DiseaseEntity:pheochromocytoma
- PreviousTesting:RET
- CivicName:R167W(c.499C>T)
- InheritancePattern:AutosomalDominant
- VHL Hypothesis Annotation
- AminoAcidChange:ARGtoTRP
- FamilyPedigree
- ClinVarID:2218
- Ethnicity:Spanish
- Familial
- ClinVarID:Yes
- AgeOfPresentation:pheochromocytoma:19
- AssumedRefSeq:AF010238.1
- inferred_gene_hgnc:12687
- ProteinPosition:167
- MutationType:missense_variant;transition
- inferred_gene_source:ClinVar
- cDNAposition:499
Annotators
URL
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link.springer.com link.springer.com
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nucleotide 500 (exon 1) resulting in an Arg167Glu
At age 14 the patient presented with a pancreatic neuroendocrine tumor that was resected. At age 19 she had hemangiomas of the fourth ventricle and cervical spinal cord which were operated. At age 27 it was noted that multiple solid tumors in the pancreas had gradually increased in size (the tumor in pancreatic head had a max size of 4.1cm) and she underwent a total pancreatectomy where pathological investigation of these tumors supported a diagnosis of well-differentiated neuroendocrine carcinoma. At age 30 she was found to have renal cell carcinoma and she underwent a nephrectomy. DNA from peripheral blood cells found a G to A point mutation at neucleotide 500 in exon 1 (Arg167Glu). Her father and elder brother were also diagnosed with VHLD. Her father had a history of two surgical resections for pancreatic neuroendocrine tumors and associated metastatic recurrence in the liver.
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- Sep 2026
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pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov
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32-year-old woman
Case#: 32-year old woman, onset in early twenties
DiseaseAssertion: STGD1
FamilyInfo: n/a
CasePresentingHPOs: HP:0011462, HP:0011507, HP:0000505, HP:0007722, HP:0030500, HP:0030329, HP:0030610, HP:0000575, HP:0030602
CaseHPOFreeText: Patient’s best-corrected visual acuity was OD: 20/200 and OS: 20/40. Refractive error was OD: −5.25/−0.75 × 4° and OS: −5.75/−0.50 × 133°. Flecks in macular area extended anterior to the vascular arcades and the optic disc in both eyes. Atrophic lesion in the macula with flecks observed across the posterior pole. IS/OS junction loss central macular area bilaterally. Absolute scotoma in left eye (ie total deviation −20 dB). Defect in the RPE/Bruch membrane complex was observed on SD-OCT in both eyes in the central macula. The defects in the RPE-Bruch membrane complex measured OD: 332 um and OS: 266 um in maximum horizontal diameter. Herniation of the retina through these defects into the sub-RPE/choroidal space. Abnormal thickening of the RPE in the parafoveal region. Normal amplitudes and implicit times in both rod and cone photoreceptor systems were detected by ERG.
CaseNotHPOs: HP:0000510, HP:0007984
CaseNotHPOFreeText: Normal amplitudes and implicit times in both rod and cone photoreceptor systems were detected by ERG. There was no evidence of sub-RPE choroidal neovascularization (CNV), pigment epithelial defects (PED) or subretinal fluid.
Genotyping Method: ABCR 600 micro-array chip
PreviouslyPublished: n/a
Variant: NM_000350.3(ABCA4):c.5714+5G>A
ClinVar: 99403
SupplementalData: n/a
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48-year-old man
Case#:48-year old man, onset at 13-years old
DiseaseAssertion: STGD1
FamilyInfo: n/a
CasePresentingHPOs: HP:0003621, HP:0025147, HP:0011507, HP:0030329, HP:0030610, HP:0007722, HP:0007703, HP:0007663
CaseHPOFreeText: BCVA was 20/200 bilaterally and refractive error was OD: −1.50/+0.50 × 149° and OS: −1.50/+0.25 × 161°. Hyperautofluorescent transitional zone in each eye more pronounced in right eye. The left eye showed a complete defect of the RPE-Bruch membrane complex with herniation of the outer retina. Maximum horizontal diameter of this RPE-Bruch membrane complex defect was 266um.
CaseNotHPOs: HP:0000510, HP:0000548, HP:0007984
CaseNotHPOFreeText: No defect observed in the RPE and Bruch membrane in right eye. Patient had normal cone and rod responses on ERG
Genotyping Method: ABCR 600 micro-array chip
PreviouslyPublished: n/a
Variant: NM_000350.3(ABCA4):c.4216C>T (p.His1406Tyr), NM_000350.3(ABCA4):c.5882G>A (p.Gly1961Glu)
ClinVar: 99259, 7888
SupplementalData: n/a
Tags
- ClinGen ABCA4 Annotations
- Zygosity:Heterozygous
- Individual
- DecreasedERGResponses
- FundusAutofluorescence
- InheritancePattern:AutosomalRecessive
- Scotoma
- DiseaseEntity:STGD1
- CaseInfo
- ClinVarID:99259
- inferred_gene_hgnc:4057
- Zygosity:NoZygosityAssertion
- Funduscopy
- MacularFlecks
- BeatenBronzeAppearance
- PreviousTesting
- inferred_gene_hgnc:986
- DecreasedCentralVA
- MacularAtrophy
- inferred_gene_source:ClinVar
- ClinVarID:99403
- ClinVarID:7888
Annotators
URL
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pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov
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man in hismid-40s
Case#: Male, mid-40s
DiseaseAssertion: STGD1
FamilyInfo: Retinal disease reported in sibling and material grandfather. Mother exhibited decreased visual acuity, BEM in right eye, and tapetal reflex in both eyes.
CasePresentingHPOs: HP:0000622, HP:0000613, HP:0000662, HP:0011504, HP:0007663, HP:0011463
CaseHPOFreeText: n/a
CaseNotHPOs: HP:0007843, HP:0011507
CaseNotHPOFreeText: Autofluorescence(qAF): 381.5. The Case's qAF was noted to be in the range observed in healthy eyes, and also lower than many other STGD1 patients with the same age. There were no flecks, intraretinal pigment migration, retinal vessel attenuation, or optic nerve pallor (Figure 1).
Genotyping Method: Sanger Sequencing
PreviouslyPublished: n/a
Variant: NM_000350.3(ABCA4):c.1411G>A (p.Glu471Lys), NM_001034853.2(RPGR):c.3070G>T (p.Glu1024Ter)
ClinVar: 99052, 1275798
SupplementalData: n/a
Tags
- ClinGen ABCA4 Annotations
- Zygosity:Heterozygous
- Individual
- ClinVarID:99052
- FundusAutofluorescence
- FamilyInfo
- InheritancePattern:AutosomalRecessive
- PigmentaryRetinopathyAttenuatedVessels
- DiseaseEntity:STGD1
- CaseInfo
- MultipleGeneVariants
- Bull’sEyeMaculopathy
- inferred_gene_hgnc:886
- NightBlindness
- MacularFlecks
- PreviousTesting
- DecreasedCentralVA
- inferred_gene_source:ClinVar
Annotators
URL
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onlinelibrary.wiley.com onlinelibrary.wiley.com
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66-year-old man
Case#: Patient 66yo, M, Japan, Symptoms in teens
DiseaseAssertion: Stargardt (STGD) Heterozygous, Autosomal recessive
FamilyInfo: No family with similar symptoms
CasePresentingHPOs: HP:0008002, HP:0007722, HP:0000610, HP:0000602
CaseHPOFreeText: Ring shaped paracentral scotoma
CaseNotHPOs: HP: 0030329, HP:0000608, HP:0000493
CaseNotHPOFreeText: Well preserved foveal function, well preserved retinal, and normal thickness RPE
Genotyping Method: N/A
PreviouslyPublished: 4 other polymorphisms
Variant: c.839T>C p.Met280Thr Heterozygous
ClinVar: 1349490
SupplementalData: see tables 1 for gene variant and found polymorphisms
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pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov
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The proband (II-1), a 43-year-old man
Case#: 43-year old man, German descent, onset within first decade of life
DiseaseAssertion: STGD1
FamilyInfo: Family pedigree shown in Figure 1.
CasePresentingHPOs: HP:0011463, HP:0000533, HP:0000580, HP:0030500, HP:0011507, HP:0000548, HP:0000510, HP:0007703, HP:0007663, HP:0000512, HP:0000610
CaseHPOFreeText: Retinal vessels were visibly attenuated.
CaseNotHPOs: n/a
CaseNotHPOFreeText: Peripapillary region around the optic nerve had no disease related changes.
Genotyping Method: Illumina MiSeq platform, Array-CGH analysis
PreviouslyPublished: n/a
Variant: NM_000350.3(ABCA4):c.161G>A (p.Cys54Tyr), NM_000350.3(ABCA4):c.4539+2028C>T
ClinVar: 99065, 236116
SupplementalData: n/a
Tags
- PeripapillarySparing
- ClinGen ABCA4 Annotations
- Zygosity:CompoundHeterozygous
- Individual
- DecreasedERGResponses
- FamilyInfo
- FundusAutofluorescence
- InheritancePattern:AutosomalRecessive
- PigmentaryRetinopathyAttenuatedVessels
- DiseaseEntity:STGD1
- ClinVarID:236116
- CaseInfo
- inferred_gene_hgnc:1100
- Funduscopy
- MacularFlecks
- ClinVarID:99065
- DecreasedCentralVA
- MacularAtrophy
- inferred_gene_source:ClinVar
- Chorioretinopathy
Annotators
URL
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onlinelibrary.wiley.com onlinelibrary.wiley.com
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A 66-year-old man
Case#: Patient 66yo, M, Japan, Symptoms in teens
DiseaseAssertion: Stargardt (STGD) Heterozygous, Autosomal recessive
FamilyInfo: No family with similar symptoms
CasePresentingHPOs: HP:0008002, HP:0007722, HP:0000610, HP:0000602
CaseHPOFreeText: Ring shaped paracentral scotoma
CaseNotHPOs: HP: 0030329, HP:0000608, HP:0000493
CaseNotHPOFreeText: Well preserved foveal function, well preserved retinal, and normal thickness RPE
Genotyping Method: N/A
PreviouslyPublished: 4 other polymorphisms
Variant: c.839T>C p.Met280Thr Heterozygous
ClinVar: 1349490
SupplementalData: see tables 1 for gene variant and found polymorphisms
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pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov
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48-year-old woman
Case#: Patient female, 48y, ethnicity not reported
DiseaseAssertion: Stargardt disease (STGD1) with unusual phenotype resembling pattern dystrophy
FamilyInfo: autosomal recessive inheritance; segregation analysis confirms each parent carries one variant (heterozygous). Pedigree shown in Figure 3. Proband is compound heterozygous for ABCA4 variants.
CasePresentingHPOs: HP:0007663, HP:0007754, HP:0030636, HP:0000548
CaseHPOFreeText: mild visual impairment (BCVA 20/25 and 20/20), perifoveal yellow fleck-like lesions, hyperautofluorescent lesions with lipofuscin accumulation, foveal sparing, subretinal material accumulation, phenotype resembling pattern dystrophy, bilateral macular involvement, decreased p50 values on pattern ERG
CaseNotHPOs: HP:0000510 (normal ERG responses except pattern ERG component)
CaseNotHPOFreeText: normal full-field ERG (scotopic and photopic responses), normal electrooculography, preserved outer retina structure, minimal photoreceptor disruption at fovea
Genotyping Method: targeted next-generation sequencing (Illumina NextSeq500) with SeqCap EZ enrichment panel; Sanger sequencing used for confirmation and segregation analysis
PreviouslyPublished: n/a
Variant: ABCA4 NM_000350.2: c.428C>T (p.Pro143Leu); c.3113C>T (p.Ala1038Val)
ClinVar: 99273; 7894
CAID: n/a
SupplementalData: clinical imaging and genetic/segregation data in supplemental data (Figures 1–3, Table 1)
Tags
- ClinGen ABCA4 Annotations
- Zygosity:CompoundHeterozygous
- DecreasedERGResponses
- AlleleOrigin:Germline
- FamilyInfo
- ClinVarID:99273
- FundusAlbipunctatus
- InheritancePattern:AutosomalRecessive
- DiseaseEntity:STGD1
- SupplementalData
- ClinVarID:7894
- MacularFlecks
- PreviousTesting
- inferred_gene_hgnc:986
- DecreasedCentralVA
- inferred_gene_source:ClinVar
Annotators
URL
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pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov
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The proband (K206–2) was 25-years-old
Case#: 25-year old female, juvenile onset
DiseaseAssertion: STGD1
FamilyInfo: Figure 1 shows family pedigree. Table 1 shows clinical features of a Chinese pedigree. Cosegregation analysis was done and shown in Figure 1A, C.
CasePresentingHPOs: HP:0007663, HP:0007722, HP:0007401, HP:0030329, HP:0030610, HP:0003621, HP:0011507, HP:0007984
CaseHPOFreeText: The uncorrected visual acuity of each eye was 20/400, which has progressively decreased for 13 years.
CaseNotHPOs: n/a
CaseNotHPOFreeText: The retinal vessels were normal.
Genotyping Method: Whole Exome Sequencing, Sanger Sequencing
PreviouslyPublished: n/a
Variant: NM_000350.3(ABCA4):c.3523-2A>G, NM_000350.3(ABCA4):c.5646G>A (p.Met1882Ile)
ClinVar: 866764, 377407
SupplementalData: n/a
Tags
- inferred_gene_hgnc:53
- ClinGen ABCA4 Annotations
- ClinVarID:377407
- Zygosity:CompoundHeterozygous
- Individual
- DecreasedERGResponses
- MacularFlecks
- InheritancePattern:AutosomalRecessive
- ClinVarID:866764
- PigmentaryRetinopathyAttenuatedVessels
- DecreasedCentralVA
- DiseaseEntity:STGD1
- MacularAtrophy
- inferred_gene_source:ClinVar
- CaseInfo
Annotators
URL
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journals.healio.com journals.healio.com
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A 37-year-old East Asian woman
Case#: Patient 37 yo, F, Eastern Asian, onset at 8yo (early onset), Heterozygous, AR inheritance patterns
DiseaseAssertion:Retinitis Pigmentosa (RP)
FamilyInfo: Two brothers with RP and father with poor vision at 30 yo but no formal diagnosis
CasePresentingHPOs: HP:0003581, HP:0007737, HP:0000510, HP:000133
CaseHPOFreeText: N/A
CaseNotHPOs: HP: 0000007, HP:0007663, HP:0000505, HP:0000662
CaseNotHPOFreeText: N/A
Genotyping Method: N/A
PreviouslyPublished: Panel of genes; RP1L1, RP-GRIP1, ABCA4, and GRM6
Variant: c.5501T>C p.(Met1019Ille)
ClinVar: 1481089
SupplementalData: see tables 1 and 2 for genetic variant panel
Tags
- SupplementalData
- ClinGen ABCA4 Annotations
- Zygosity:CompoundHeterozygous
- (5) DiseaseEntity:RP19
- ExperimentalAssay
- FundusAutofluorescence
- FamilyInfo
- inferred_gene_hgnc:3587
- InheritancePattern:AutosomalRecessive
- MacularFlecks
- RPEMottling
- ClinVarID:1481089
- inferred_gene_source:ClinVar
Annotators
URL
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