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NM_000551.4(VHL):c.335A>G (p.Tyr112Cys) AND multiple conditions

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Jan 21, 2024
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:
RCV000631262.8

Allele description [Variation Report for NM_000551.4(VHL):c.335A>G (p.Tyr112Cys)]

NM_000551.4(VHL):c.335A>G (p.Tyr112Cys)

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.335A>G (p.Tyr112Cys)
HGVS:
  • NC_000003.12:g.10142182A>G
  • NG_008212.3:g.5548A>G
  • NM_000551.4:c.335A>GMANE SELECT
  • NM_001354723.2:c.335A>G
  • NM_198156.3:c.335A>G
  • NP_000542.1:p.Tyr112Cys
  • NP_000542.1:p.Tyr112Cys
  • NP_001341652.1:p.Tyr112Cys
  • NP_937799.1:p.Tyr112Cys
  • LRG_322t1:c.335A>G
  • LRG_322:g.5548A>G
  • LRG_322p1:p.Tyr112Cys
  • NC_000003.11:g.10183866A>G
  • NM_000551.2:c.335A>G
  • NM_000551.3:c.335A>G
  • p.[Tyr112Cys]
Protein change:
Y112C
Links:
dbSNP: rs869025633
NCBI 1000 Genomes Browser:
rs869025633
Molecular consequence:
  • NM_000551.4:c.335A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354723.2:c.335A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_198156.3:c.335A>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

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000752290Invitae
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Pathogenic
(Jan 21, 2024) 		germlineclinical testing

PubMed (7)
[See all records that cite these PMIDs]

Help

Summary from all submissions

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

Citations

PubMed

From arterial hypertension complications to von Hippel-Lindau syndrome diagnosis.

Kozaczuk S, Ben-Skowronek I.

Ital J Pediatr. 2015 Aug 13;41:56. doi: 10.1186/s13052-015-0158-y.

PubMed [citation]
PMID:
26268347
PMCID:
PMC4535675

Germline mutations in the Von Hippel-Lindau disease (VHL) gene in families from North America, Europe, and Japan.

Zbar B, Kishida T, Chen F, Schmidt L, Maher ER, Richards FM, Crossey PA, Webster AR, Affara NA, Ferguson-Smith MA, Brauch H, Glavac D, Neumann HP, Tisherman S, Mulvihill JJ, Gross DJ, Shuin T, Whaley J, Seizinger B, Kley N, Olschwang S, Boisson C, et al.

Hum Mutat. 1996;8(4):348-57.

PubMed [citation]
PMID:
8956040
See all PubMed Citations (7)

Details of each submission

From Invitae, SCV000752290.6

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (7)

Description

This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 112 of the VHL protein (p.Tyr112Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of von Hippel-Lindau syndrome type 2C (PMID: 26268347; Invitae). ClinVar contains an entry for this variant (Variation ID: 223189). 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 with a positive predictive value of 95%. This variant disrupts the p.Tyr112 amino acid residue in VHL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8956040, 10408776, 10823831, 19030229, 21204227). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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: May 7, 2024