NM_000551.4(VHL):c.538A>G (p.Ile180Val) AND multiple conditions

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Jan 24, 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:: RCV000524495.10

Allele description [Variation Report for NM_000551.4(VHL):c.538A>G (p.Ile180Val)]

NM_000551.4(VHL):c.538A>G (p.Ile180Val)

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.538A>G (p.Ile180Val)

HGVS:

NC_000003.12:g.10149861A>G
NG_008212.3:g.13227A>G
NG_046756.1:g.7623A>G
NM_000551.4:c.538A>GMANE SELECT
NM_001354723.2:c.*92A>G
NM_198156.3:c.415A>G
NP_000542.1:p.Ile180Val
NP_000542.1:p.Ile180Val
NP_937799.1:p.Ile139Val
LRG_322t1:c.538A>G
LRG_322:g.13227A>G
LRG_322p1:p.Ile180Val
NC_000003.11:g.10191545A>G
NM_000551.3:c.538A>G
P40337:p.Ile180Val

Protein change:

I139V

Links:

UniProtKB: P40337#VAR_005770; dbSNP: rs377715747

NCBI 1000 Genomes Browser:

rs377715747

Molecular consequence:

NM_001354723.2:c.*92A>G - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_000551.4:c.538A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_198156.3:c.415A>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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000259642	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 24, 2024)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 7987306, 9681856, 17024664, 19408298, 21715564, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000259642

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jan 24, 2024)

germline

clinical testing

PubMed (6)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Identification of intragenic mutations in the von Hippel-Lindau disease tumour suppressor gene and correlation with disease phenotype.

Crossey PA, Richards FM, Foster K, Green JS, Prowse A, Latif F, Lerman MI, Zbar B, Affara NA, Ferguson-Smith MA, et al.

Hum Mol Genet. 1994 Aug;3(8):1303-8.

PubMed [citation]

PMID:: 7987306

Genotype-phenotype correlations in von Hippel-Lindau disease.

Neumann HP, Bender BU.

J Intern Med. 1998 Jun;243(6):541-5. Review.

PubMed [citation]

PMID:: 9681856

See all PubMed Citations (6)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000259642.10

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 180 of the VHL protein (p.Ile180Val). This variant is present in population databases (rs377715747, gnomAD 0.003%). This missense change has been observed in individual(s) with von Hipple-Lindau (VHL) disease (PMID: 7987306, 9681856, 17024664, 19408298). This variant is also known as 751A>G, Ile251Val. ClinVar contains an entry for this variant (Variation ID: 161401). 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%. Experimental studies have shown that this missense change does not substantially affect VHL function (PMID: 21715564). 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Nov 3, 2024

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