NM_000551.4(VHL):c.349T>C (p.Trp117Arg) AND multiple conditions

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jan 20, 2022
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:: RCV003017971.3

Allele description [Variation Report for NM_000551.4(VHL):c.349T>C (p.Trp117Arg)]

NM_000551.4(VHL):c.349T>C (p.Trp117Arg)

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.349T>C (p.Trp117Arg)

HGVS:

NC_000003.12:g.10146522T>C
NG_008212.3:g.9888T>C
NG_046756.1:g.4284T>C
NM_000551.4:c.349T>CMANE SELECT
NM_001354723.2:c.*18-3265T>C
NM_198156.3:c.341-3265T>C
NP_000542.1:p.Trp117Arg
NP_000542.1:p.Trp117Arg
LRG_322t1:c.349T>C
LRG_322:g.9888T>C
LRG_322p1:p.Trp117Arg
NC_000003.11:g.10188206T>C
NM_000551.3:c.349T>C
NR_176335.1:n.678T>C

Protein change:

W117R

Molecular consequence:

NM_001354723.2:c.*18-3265T>C - intron variant - [Sequence Ontology: SO:0001627]
NM_198156.3:c.341-3265T>C - intron variant - [Sequence Ontology: SO:0001627]
NM_000551.4:c.349T>C - 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
SCV003302069	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 20, 2022)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 18685280, 24581539, 28388566, 30477447, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003302069

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 20, 2022)

germline

clinical testing

PubMed (5)
[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

Germline mutation in the von Hippel-Lindau gene in Kuwait: a clinical and molecular study.

AlFadhli SM, Mohammed B, Yassin A.

Med Princ Pract. 2008;17(5):395-9. doi: 10.1159/000141504. Epub 2008 Aug 6.

PubMed [citation]

PMID:: 18685280

Higher prevalence of novel mutations in VHL gene in Chinese Von Hippel-Lindau disease patients.

Wang X, Zhang N, Ning X, Li T, Wu P, Peng S, Fan Y, Bu D, Gong K.

Urology. 2014 Mar;83(3):675.e1-5. doi: 10.1016/j.urology.2013.09.069.

PubMed [citation]

PMID:: 24581539

See all PubMed Citations (5)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003302069.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tryptophan, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 117 of the VHL protein (p.Trp117Arg). This missense change has been observed in individual(s) with von Hippel-Lindau syndrome (PMID: 30477447). It has also been observed to segregate with disease in related individuals. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Trp117 amino acid residue in VHL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18685280, 24581539, 28388566, 30477447; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.

#	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: Sep 29, 2024

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