NM_000551.4(VHL):c.293A>C (p.Tyr98Ser) AND multiple conditions

Clinical significance:Pathogenic (Last evaluated: Feb 4, 2019)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV001064921.2

Allele description [Variation Report for NM_000551.4(VHL):c.293A>C (p.Tyr98Ser)]

NM_000551.4(VHL):c.293A>C (p.Tyr98Ser)

Gene:
VHL:von Hippel-Lindau tumor suppressor [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
3p25.3
Genomic location:
Preferred name:
NM_000551.4(VHL):c.293A>C (p.Tyr98Ser)
HGVS:
  • NC_000003.12:g.10142140A>C
  • NG_008212.3:g.5506A>C
  • NM_000551.3:c.293A>C
  • NM_000551.4:c.293A>CMANE SELECT
  • NM_001354723.2:c.293A>C
  • NM_198156.3:c.293A>C
  • NP_000542.1:p.Tyr98Ser
  • NP_000542.1:p.Tyr98Ser
  • NP_001341652.1:p.Tyr98Ser
  • NP_937799.1:p.Tyr98Ser
  • LRG_322t1:c.293A>C
  • LRG_322:g.5506A>C
  • LRG_322p1:p.Tyr98Ser
  • NC_000003.11:g.10183824A>C
  • NC_000003.11:g.10183824A>C
  • p.[Tyr98Ser]
Protein change:
Y98S
Links:
dbSNP: rs864321643
NCBI 1000 Genomes Browser:
rs864321643
Molecular consequence:
  • NM_000551.3:c.293A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_000551.4:c.293A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354723.2:c.293A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_198156.3:c.293A>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Erythrocytosis, familial, 2 (ECYT2)
Synonyms:
POLYCYTHEMIA, CHUVASH TYPE; POLYCYTHEMIA, VHL-DEPENDENT
Identifiers:
MONDO: MONDO:0009892; MedGen: C1837915; Orphanet: 238557; OMIM: 263400
Name:
Von Hippel-Lindau syndrome (VHLS)
Synonyms:
VHL syndrome; Von Hippel-Lindau
Identifiers:
MONDO: MONDO:0008667; MedGen: C0019562; Orphanet: 892; OMIM: 193300

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV001229857Invitaecriteria provided, single submitter
Pathogenic
(Feb 4, 2019)
germlineclinical testing

PubMed (11)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Germline mutations and genotype-phenotype correlation in Asian Indian patients with pheochromocytoma and paraganglioma.

Pandit R, Khadilkar K, Sarathi V, Kasaliwal R, Goroshi M, Khare S, Nair S, Raghavan V, Dalvi A, Hira P, Fernandes G, Sathe P, Rojekar A, Malhotra G, Bakshi G, Prakash G, Bhansali A, Walia R, Kamalanathan S, Sahoo J, Desai A, Bhagwat N, et al.

Eur J Endocrinol. 2016 Oct;175(4):311-23. doi: 10.1530/EJE-16-0126. Erratum in: Eur J Endocrinol. 2016 Dec;175(6):X3.

PubMed [citation]
PMID:
27539324

Genotype phenotype correlation in Asian Indian von Hippel-Lindau (VHL) syndrome patients with pheochromocytoma/paraganglioma.

Lomte N, Kumar S, Sarathi V, Pandit R, Goroshi M, Jadhav S, Lila AR, Bandgar T, Shah NS.

Fam Cancer. 2018 Jul;17(3):441-449. doi: 10.1007/s10689-017-0058-y.

PubMed [citation]
PMID:
29124493
See all PubMed Citations (11)

Details of each submission

From Invitae, SCV001229857.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (11)

Description

This sequence change replaces tyrosine with serine at codon 98 of the VHL protein (p.Tyr98Ser). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and serine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals affected with von Hippel-Lindau (VHL) syndrome and to segregate in an affected family (PMID: 27539324, 29124493, 28388566). ClinVar contains an entry for this variant (Variation ID: 219160). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant disrupts the p.Tyr98 amino acid residue in VHL. Another variant that disrupts this residue has been observed in individuals with VHL-related conditions (PMID: 7759077, 7728151, 10408776, 21204227, 19763184, 19336503, 11483638), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Oct 25, 2021

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