PatientID: 2178

KindredID: 113

Case: Sex Unknown, Age Unknown, French

DiseaseAssertion: VHL

FamilyInfo: N/A

CohortInfo: Families were recruited from the French VHL Registry. Enrolment in the study required identification of the germline VHL mutation (currently 85% of the families included in the French VHL Registry) and available data regarding renal phenotype. A total of 126 families fulfilled these criteria.

CasePresentingHPOs: HP:0005584 (Renal cell carcinoma)

CaseHPOFreeText: Moderate renal disease (less than five solid lesions requiring surgical treatment, either unilateral or bilateral). Individual RCC phenotype is noted as positive.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Phenotype and genotype information can be found in Supplementary Table S1.

Variant: p.V87A (c.260T>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA351750654, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.260T%3EC

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: V87A (c.260T>C)

MultipleGeneVariants: N/A

Case5: Female, 10m, Chinese, part of Family 1

HPOsFreeText: (at 20 days) 1.38 C4 umol/L, 0.19 C4/C2, 1.79 C4/C3, 2.58 (mmol/mol creatinine) urine isobutyrylglycine

Case5 (Level 2):

CasePreviousTesting: same as group

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant1: NM_014384.2:c.286G>A (p.Gly96Ser)

ClinVar: n/a

CAID: CA6372895

gnomAD: 0.001453 (East Asian)

Variant2: NM_014384.2:c.1092+1G>A

ClinVar: n/a

CAID: CA6373205

gnomAD: 0.00005790 (Latino)

CaseAddInfo: younger sister of patient 6, trans heterozygous, inherited one allele from each parent

Case4: Male, 1y 2m, Chinese

HPOsFreeText: (at 21 days) 0.77 C4 umol/L, 0.07 C4/C2, 0.86 C4/C3

NotHPOsFreeText: normal urine isobutyrylglycine

Case4 (Level 2):

CasePreviousTesting: same as group

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant1: NM_014384.2:c.286G>A (p.Gly96Ser)

ClinVar: n/a

CAID: CA6372895

gnomAD: 0.001453 (East Asian)

Variant2: NM_014384.2:c.444G>T (p.Pro148=)

ClinVar: n/a

CAID: CA6372946

gnomAD: 0.0002772 (Other)

CaseAddInfo: trans heterozygous, inherited one allele from each parent

Case1: Female, 1y 7m, Chinese

HPOsFreeText: (at 13 days) C4 1.31 umol/L, C4/C2 0.21, C4/C3 1.96

NotHPOsFreeText: normal urine isobutyrylglycine

Case1 (Level 2)

CasePreviousTesting: same as group

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant1: NM_014384.2:c.235C>G (p.Arg79Gly)

ClinVar: n/a

CAID: CA6372884

gnomAD: 0.0002718 (East Asian)

Variant2: NM_014384.2:c.1000C>T (p.Arg334Cys)

ClinVar: n/a

CAID: CA6373194

gnomAD: 0.0003007 (East Asian)

CaseAddInfo: trans heterozygous, inherited one allele from each parent

Case2: Male, 1y 7m, Chinese

HPOsFreeText: (at 11 days) 1.69 C4 umol/L, 0.19 C4/C2, 2.38 C4/C3

NotHPOsFreeText: normal urine isobutyrylglycine

Case2 (Level 2)

CasePreviousTesting: same as group

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant: NM_014384.2:c.286G>A (p.Gly96Ser)

ClinVar: n/a

CAID: CA6372895

gnomAD: 0.001453 (East Asian)

CaseAddInfo:

Case7: Male, 6m, Chinese

CasePresentingHPOs: HP:0002248, HP:0001290, HP:0008872, HP:0002572 (haematemesis, hypotonia, feeding difficulties in infancy, recurrent vomiting)

HPOsFreeText: (at 19 days) 1.01 C4 umol/L, 0.38 C4/C2, 1.61 C4/C3

NotHPOsFreeText: normal urine isobutyrylglycine

Case7 (Level 2):

CasePreviousTesting: same as group

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant1: NM_014384.2:c.444G>T (p.Pro148=)

ClinVar: n/a

CAID: CA6372946

gnomAD: 0.0002772 (Other)

Variant2: NM_014384.2:c.1176G>T (p.Arg392Ser)

ClinVar: n/a

CAID: CA6373249

gnomAD: 0.0001088 (East Asian)

CaseAddInfo: trans heterozygous, inherited one allele from each parent

Case3: Female, 1y 5m, Chinese

HPOsFreeText: (at 21 days) 1.96 C4, 0.17 C4/C2, 2.09 C4/C3

NotHPOsFreeText: normal urine isobutyrylglycine

Case3 (Level 2):

CasePreviousTesting: same as group

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant: NM_014384.2:c.286G>A (p.Gly96Ser)

ClinVar: n/a

CAID: CA6372895

gnomAD: 0.001453 (East Asian)

CaseAddInfo:

Case6: Male, 8y 11m, Chinese, part of Family 1

CasePresentingHPOs: HP:0000750, HP:0001328 (speech delay, learning disability)

HPOsFreeText: (at 8y 8m) 1.07 C4 umol/L, 0.13 C4/C2, 1.20 C4/C3

Case6 (Level 2):

CasePreviousTesting: same as group

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant1: NM_014384.2:c.286G>A (p.Gly96Ser)

ClinVar: n/a

CAID: CA6372895

gnomAD: 0.001453 (East Asian)

Variant2: NM_014384.2:c.1092+1G>A

ClinVar: n/a

CAID: CA6373205

gnomAD: 0.00005790 (Latino)

CaseAddInfo: older brother of patient 5. Had not undergone expanded NBS at birth but presented with symptoms by age 8 and was diagnosed later since his younger sister has IBDHD. Trans heterozygous, inherited one allele from each parent

Case11: Male, 3 wk at initiation of follow up, African American ancestry

HPOsFreeText: NBS C4-acylcarnitine 1.4 umol/L, lasma C4 acylcarnitine 1.87 umol/L, in vitro probe isoC4-acylcarnitine 0.053 umol/ g protein

NotHPOsFreeText: normal in vitro probe C4-aclycarnitine, normal urine isobutyrylglycine, normal urine C4-acylcarnitine, normal urine C4/C3 ratio

CaseAddInfo: mild biochemical phenotype observed. Suggested to be at minimum a carrier of IBD deficiency- however presence of promoter mutation, large deletion, or splice-site alteration undetectable by direct gene sequencing cannot be ruled out.

Case11 (Level 2)

CasePreviousTesting: same as group

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant2: NM_014384.2(ACAD8):c.1129G>A (p.Gly377Ser)

ClinVar: 5356

CAID: CA117435

gnomAD: 0.0001551 (European non-Finnish)

CaseAddInfo: heterozygous for mutation

Case6: Female, 16 days at initiation of follow up, European ancestry

HPOsFreeText: NBS C4-acylcarnitine 2.0 umol/L, Plasma C4-acylcarnitine 1.36 umol/L, in vitro probe isoC4-acylcarnitine 0.160 umol/g protein, in vitro probe C4-acylcarnitine 0.150 umol/g protein, urine c4 acylcarnitine 19.13 mmol/mol creatinine, urine C4/C3 ratio 101

CaseNotHPOs: normal urine isobutyryglycine

CaseAddInfo: no data for clinical condition or SCAD gene variants

Case6 (Level 2)

CasePreviousTesting: same as group

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant1: NM_014384.2(ACAD8):c.958G>A (p.Ala320Thr)

ClinVar: 372297

CAID: CA6373180

gnomAD: 0.001725 (European Finnish)

Variant2: NM_014384.2(ACAD8):c.1129G>A (p.Gly377Ser)

ClinVar: 5356

CAID: CA117435

gnomAD: 0.0001551 (European non-Finnish)

CaseAddInfo: compound heterozygote, specified allele 1 and 2 but not maternal and paternal. no potential splice site alteration

Case7a: Male, 7 days at initiation of follow up, Hispanic ancestry

HPOsFreeText: NBS C4-acylcarnitine 2.2 umol/L, plasma C4-acylcarnitine 2.09 umol/L, in vitro probe isoC4-acylcarnitine 0.070 umol/g protein, urine C4-acylcarnitine 3.58 mmol/mol creatinine, Urine C4/C3 ratio 130.

CaseNotHPOs: normal in vitro probe C4-acylcarnitine, normal urine isobutyrylglycine,

CaseAddInfo: younger brother of patient 7b, part of Family2, unremarkable clinical condition

Case7a (Level 2)

CasePreviousTesting: same as group

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant1: NM_014384.2:c.687T>G (p.Phe229Leu)

ClinVar: n/a

CAID: CA6373030

gnomAD: 0.00008673 (Latino)

Variant2: NM_014384.2(ACAD8):c.1129G>A (p.Gly377Ser)

ClinVar: 5356

CAID: CA117435

gnomAD: 0.0001551 (European non-Finnish)

CaseAddInfo: no potential splice site alteration, no data for SCAD gene variants

Case1: Female, 9 days at follow up, North African ancestry

CasePresentingHPOs: HP:0002013, HP:0001944,HP:0031123, HP:0000388 (emesis, dehydration, recurrent gastroenteritis, otitis media)

HPOsFreeText: NBS C4-acylcarnitine 2.9 umol/L, plasma C4 acylcarnitine 1.35 umol/L, isoC4-acylcarnitine 0.090 umol/g protein,

CaseNotHPOs:

NotHPOsFreeText: normal urine isobutyrylglycine

CaseAddInfo: repeatedly hospitalized during first 2 years of life.

CasePMIDs:

Case (Level 2)

CasePreviousTesting: same as group

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant: NM_014384.2(ACAD8):c.988C>T (p.Arg330Trp)

ClinVar: 5357

CAID: CA117438

gnomAD: 0.00006155 (African)

CaseAddInfo: homozygous mutations

Case4: Female, 2 wks at initation of follow up, European ancestry

HPOsFreeText: NBS C4-acylcarnitine 2.0 umol/L, Plasma C4-acylcarnitine 1.52 umol/L

CaseAddInfo: no data for urine excretion, unremarkable clinical condition

Case4 (Level 2)

CasePreviousTesting: same as group

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant1: NM_014384.2:c.443C>T (p.Pro148Leu)

ClinVar: n/a

CAID: CA6372945

gnomAD: not in gnomAD

Variant2: NM_014384.2(ACAD8):c.455T>C (p.Met152Thr)

ClinVar: 5355

CAID: CA117433

gnomAD: 0.0001395 (European Non-Finnish)

CaseAddInfo: compound heterozygote, indicated alleles 1 and 2 but not specified maternal and paternal, potential splice site variant of ACAD8 at exon3 (+3A>G)

Case3a: Male, 5d at initiation of follow up, East Indian Ancestry, sibling of Case 3b (family 1)

HPOsFreeText: NBS C4-acylcarnitine 2.4 umol/L, Plasma C4-acylcarnitine 1.14 umol/L, in vitro probe isoC4-acylcarnitine 0.133 umol/ g protein,

NotHPOsFreeText: normal urine isobutyrylglycine ug/mg creatinine

CaseAddInfo: unremarkable clinical condition

Case3a (Level 2)

CasePreviousTesting: same as group

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant: NM_014384.2(ACAD8):c.867C>A (p.His289Gln)

ClinVar: 5358

CAID: CA117441

gnomAD: not in gnomAD

CaseAddInfo: homozygous mutations

Case9: Male, 2 mo at initiation of follow up, Hispanic ancestry

HPOsFreeText: NBS C4-acylcarnitine 1.8 umol/L, Plasma C4-acylcarnitine 3.28, umol/L, in vitro probe isoC4-acylcarnitine 0.074 umol/g protein, urine C4-acylcarnitine 7.86 mmol/mol creatinine, Urine C4/C3 ratio 63

NotHPOsFreeText: normal urine isobutyrylglycine

CaseAddInfo: unremarkable clinical condition

Case9 (Level 2)

CasePreviousTesting: same as group

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant: NM_014384.2(ACAD8):c.233T>C (p.Met78Thr)

ClinVar: 430160

CAID: CA6372883

gnomAD: n/a

CaseAddInfo: homozygous variants, no potential splice site alterations, no data for ACADS (SCAD-deficient) gene variants

Case2: Female, 3 m at initiation of follow up, European ancestry

HPOsFreeText: NBS C4-acylcarnitine 2.5 umol/L, plasma C4-acylcarnitine 10.00 umol/L, isoC4-acylcarnitine 0.120 umol/g protein, in vitro prob C4-acylcarnitine 0.220 umol/ g protein

CaseAddInfo: no data for urine excretion, unremarkable clinical condition

Case2 (Level 2)

CasePreviousTesting: same as group

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant1: NM_014384.2(ACAD8):c.289G>A (p.Gly97Arg)

ClinVar: 281037

CAID: CA6372897

gnomAD: 0.0002175 (East Asian)

Variant2: NM_014384.2(ACAD8):c.455T>C (p.Met152Thr)

ClinVar: 5355

CAID: CA117433

gnomAD: 0.0001395 (European Non-Finnish)

CaseAddInfo: compound heterozygous, potential splice-site alteration on ACAD8 at Exon 3 (+3A>G), homozygous for two common ACADS (SCAD-deficient) gene variants (625G>A/625G>A) which has 22% frequency in general population and correlates with increased accumulation of butyrylcarnitine

Case3b: Female, 9 d at initiation of follow up, East Indian ancestry, sibling of Case 3a (Family 1)

HPOsFreeText: NBS C4-acylcarnitine 2.1 umol/L, Plasma C4-acylcarnitine 2.47 umol/L, urine C4-acylcarnitine 21.66 mmol/mol creatinine, Urine C4/C3 ratio 42

NotHPOsFreeText: normal urine isobutyrylgycine ug/mg creatinine

CaseAddInfo: unremarkable clinical condition

Case3b (Level 2)

CasePreviousTesting: same as group

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant: NM_014384.2(ACAD8):c.867C>A (p.His289Gln)

ClinVar: 5358

CAID: CA117441

gnomAD: not in gnomAD

CaseAddInfo: homozygous mutations, no data for SCAD gene variants

Case8: Male, 6 wks at initiation of follow up, European ancestry

HPOsFreeText: NBS C4-acylcarnitine 1.8 umol/L, plasma C4 acylcarnitine 1.52 umol/L, in vitro probe isoC4-acylcarnitine 0.187 umol/ g protein, in vitro probe C4-acylcarnitine 0.573 umol/g protein, elevated urine C4-acylcarnitine 25.09 mmol/mol creatinine, Urine C4/C3 ratio 88

NotHPOsFreeText: normal urine isobutyryglycine

CaseAddInfo: unremarkable clinical condition

Case8 (Level 2)

CasePreviousTesting: same as group

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant1: NM_014384.2(ACAD8):c.512C>G (p.Ser171Cys)

ClinVar: 95589

CAID: CA223125

gnomAD: 0.02252 (European non-Finnish)

Variant2: NM_014384.2(ACAD8):c.455T>C (p.Met152Thr)

ClinVar: 5355

CAID: CA117433

gnomAD: 0.0001395 (European Non-Finnish)

CaseAddInfo: compound heterozygote specified allele 1 and 2, but not maternal and paternal. Potential splice-site alteration at exon 3(+3A>G). ACADS (SCAD-deficient) gene variants 625G>A/625G>A.