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NM_000551.4(VHL):c.524A>G (p.Tyr175Cys) AND multiple conditions

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Oct 10, 2023
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV000533687.9

Allele description [Variation Report for NM_000551.4(VHL):c.524A>G (p.Tyr175Cys)]

NM_000551.4(VHL):c.524A>G (p.Tyr175Cys)

Genes:
LOC107303340:3p25 von Hippel-Lindau tumor suppressor, E3 ubiquitin protein ligase Alu-mediated recombination region [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.524A>G (p.Tyr175Cys)
HGVS:
  • NC_000003.12:g.10149847A>G
  • NG_008212.3:g.13213A>G
  • NG_046756.1:g.7609A>G
  • NM_000551.4:c.524A>GMANE SELECT
  • NM_001354723.2:c.*78A>G
  • NM_198156.3:c.401A>G
  • NP_000542.1:p.Tyr175Cys
  • NP_000542.1:p.Tyr175Cys
  • NP_937799.1:p.Tyr134Cys
  • LRG_322t1:c.524A>G
  • LRG_322:g.13213A>G
  • LRG_322p1:p.Tyr175Cys
  • NC_000003.11:g.10191531A>G
  • NM_000551.3:c.524A>G
Protein change:
Y134C
Links:
dbSNP: rs193922613
NCBI 1000 Genomes Browser:
rs193922613
Molecular consequence:
  • NM_001354723.2:c.*78A>G - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
  • NM_000551.4:c.524A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_198156.3:c.401A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Chuvash polycythemia
Synonyms:
POLYCYTHEMIA, VHL-DEPENDENT; Erythrocytosis, familial, 2
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
SCV000626909Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Pathogenic
(Oct 10, 2023)
germlineclinical testing

PubMed (4)
[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

Molecular study of congenital erythrocytosis in 70 unrelated patients revealed a potential causal mutation in less than half of the cases (Where is/are the missing gene(s)?).

Bento C, Almeida H, Maia TM, Relvas L, Oliveira AC, Rossi C, Girodon F, Fernandez-Lago C, Aguado-Diaz A, Fraga C, Costa RM, Araújo AL, Silva J, Vitória H, Miguel N, Silveira MP, Martin-Nuñez G, Ribeiro ML.

Eur J Haematol. 2013 Oct;91(4):361-8. doi: 10.1111/ejh.12170. Epub 2013 Aug 20.

PubMed [citation]
PMID:
23859443

Bilateral Pheochromocytomas in a Patient with Y175C Von Hippel-Lindau Mutation.

Astapova O, Biswas A, DiMauro A, Moalem J, Hammes SR.

Case Rep Endocrinol. 2018;2018:8967159. doi: 10.1155/2018/8967159.

PubMed [citation]
PMID:
30105105
PMCID:
PMC6076969
See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000626909.8

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)

Description

This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 175 of the VHL protein (p.Tyr175Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with a personal and/or family history of VHL-associated tumors, erythrocytosis and von Hippel-Lindau (VHL) syndrome (PMID: 14722919, 23859443, 30105105; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 36905). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt VHL protein function. This variant disrupts the p.Tyr175 amino acid residue in VHL. Other variant(s) that disrupt this residue have been observed in individuals with VHL-related conditions (PMID: 14722919), which suggests that this may be a clinically significant amino acid residue. 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: Sep 29, 2024