NM_000551.4(VHL):c.484T>C (p.Cys162Arg) AND multiple conditions

Clinical significance:Pathogenic (Last evaluated: Oct 26, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV001060967.2

Allele description [Variation Report for NM_000551.4(VHL):c.484T>C (p.Cys162Arg)]

NM_000551.4(VHL):c.484T>C (p.Cys162Arg)

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.484T>C (p.Cys162Arg)
HGVS:
  • NC_000003.12:g.10149807T>C
  • NG_008212.3:g.13173T>C
  • NG_046756.1:g.7569T>C
  • NM_000551.4:c.484T>CMANE SELECT
  • NM_001354723.2:c.*38T>C
  • NM_198156.3:c.361T>C
  • NP_000542.1:p.Cys162Arg
  • NP_000542.1:p.Cys162Arg
  • NP_937799.1:p.Cys121Arg
  • LRG_322t1:c.484T>C
  • LRG_322:g.13173T>C
  • LRG_322p1:p.Cys162Arg
  • NC_000003.11:g.10191491T>C
  • NM_000551.3:c.484T>C
Protein change:
C121R
Links:
dbSNP: rs1553620313
NCBI 1000 Genomes Browser:
rs1553620313
Molecular consequence:
  • NM_001354723.2:c.*38T>C - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
  • NM_000551.4:c.484T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_198156.3:c.361T>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
SCV001225689Invitaecriteria provided, single submitter
Pathogenic
(Oct 26, 2020)
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 in the von Hippel-Lindau disease tumor suppressor gene: correlations with phenotype.

Chen F, Kishida T, Yao M, Hustad T, Glavac D, Dean M, Gnarra JR, Orcutt ML, Duh FM, Glenn G, et al.

Hum Mutat. 1995;5(1):66-75.

PubMed [citation]
PMID:
7728151

Germline mutations in the von Hippel-Lindau disease (VHL) gene in Japanese VHL. Clinical Research Group for VHL in Japan.

[No authors listed]

Hum Mol Genet. 1995 Dec;4(12):2233-7.

PubMed [citation]
PMID:
8634692
See all PubMed Citations (11)

Details of each submission

From Invitae, SCV001225689.2

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

Description

This sequence change replaces cysteine with arginine at codon 162 of the VHL protein (p.Cys162Arg). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals and families affected with von Hippel-Lindau syndrome (PMID: 7728151, 8634692, 8641976, 9681856, 8956040). This variant is also known as c.697T>C (p.Cys233Arg) in the literature. ClinVar contains an entry for this variant (Variation ID: 496067). Experimental studies have shown that this missense change impairs Elongin C binding and results in reduced apoptosis when compared to wild-type VHL protein (PMID: 28052007). A different missense substitution at this codon (p.Cys162Trp) has been determined to be pathogenic (PMID: 17350623, 19270817, 9829912, 25867206, Invitae). This suggests that the cysteine residue is critical for VHL protein function and that other missense substitutions at this position may also be pathogenic. 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: Dec 4, 2021

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