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NM_000551.4(VHL):c.227T>G (p.Phe76Cys) AND multiple conditions

Germline classification:
Uncertain significance (1 submission)
Last evaluated:
Aug 6, 2021
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:
RCV001209996.7

Allele description [Variation Report for NM_000551.4(VHL):c.227T>G (p.Phe76Cys)]

NM_000551.4(VHL):c.227T>G (p.Phe76Cys)

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.227T>G (p.Phe76Cys)
HGVS:
  • NC_000003.12:g.10142074T>G
  • NG_008212.3:g.5440T>G
  • NM_000551.4:c.227T>GMANE SELECT
  • NM_001354723.2:c.227T>G
  • NM_198156.3:c.227T>G
  • NP_000542.1:p.Phe76Cys
  • NP_000542.1:p.Phe76Cys
  • NP_001341652.1:p.Phe76Cys
  • NP_937799.1:p.Phe76Cys
  • LRG_322t1:c.227T>G
  • LRG_322:g.5440T>G
  • LRG_322p1:p.Phe76Cys
  • NC_000003.11:g.10183758T>G
  • NM_000551.3:c.227T>G
Protein change:
F76C
Links:
dbSNP: rs730882033
NCBI 1000 Genomes Browser:
rs730882033
Molecular consequence:
  • NM_000551.4:c.227T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354723.2:c.227T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_198156.3:c.227T>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
SCV001381459Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Uncertain significance
(Aug 6, 2021) 		germlineclinical testing

PubMed (6)
[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

Germline mutations in the von Hippel-Lindau (VHL) gene in patients from Poland: disease presentation in patients with deletions of the entire VHL gene.

Cybulski C, Krzystolik K, Murgia A, Górski B, Debniak T, Jakubowska A, Martella M, Kurzawski G, Prost M, Kojder I, Limon J, Nowacki P, Sagan L, Białas B, Kałuza J, Zdunek M, Omulecka A, Jaskólski D, Kostyk E, Koraszewska-Matuszewska B, Haus O, Janiszewska H, et al.

J Med Genet. 2002 Jul;39(7):E38. No abstract available.

PubMed [citation]
PMID:
12114495
PMCID:
PMC1735187

Frequency of Von Hippel-Lindau germline mutations in classic and non-classic Von Hippel-Lindau disease identified by DNA sequencing, Southern blot analysis and multiplex ligation-dependent probe amplification.

Hes FJ, van der Luijt RB, Janssen AL, Zewald RA, de Jong GJ, Lenders JW, Links TP, Luyten GP, Sijmons RH, Eussen HJ, Halley DJ, Lips CJ, Pearson PL, van den Ouweland AM, Majoor-Krakauer DF.

Clin Genet. 2007 Aug;72(2):122-9. Erratum in: Clin Genet. 2008 Apr;73(4):399.

PubMed [citation]
PMID:
17661816
See all PubMed Citations (6)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001381459.5

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (6)

Description

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant disrupts the p.Phe76 amino acid residue in VHL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12114495, 17661816, 20064270, 23632291, 27439424). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 has not been reported in the literature in individuals with VHL-related conditions. ClinVar contains an entry for this variant (Variation ID: 496051). This variant is not present in population databases (ExAC no frequency). This sequence change replaces phenylalanine with cysteine at codon 76 of the VHL protein (p.Phe76Cys). The phenylalanine residue is highly conserved and there is a large physicochemical difference between phenylalanine and cysteine.

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

Last Updated: Sep 29, 2024