NM_000551.4(VHL):c.499C>T (p.Arg167Trp) AND not provided

Germline classification:: Pathogenic (4 submissions)
Last evaluated:: May 25, 2022
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000213079.23

Allele description [Variation Report for NM_000551.4(VHL):c.499C>T (p.Arg167Trp)]

NM_000551.4(VHL):c.499C>T (p.Arg167Trp)

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.499C>T (p.Arg167Trp)

Other names:

p.R167W:CGG>TGG

HGVS:

NC_000003.12:g.10149822C>T
NG_008212.3:g.13188C>T
NG_046756.1:g.7584C>T
NM_000551.4:c.499C>TMANE SELECT
NM_001354723.2:c.*53C>T
NM_198156.3:c.376C>T
NP_000542.1:p.Arg167Trp
NP_000542.1:p.Arg167Trp
NP_937799.1:p.Arg126Trp
LRG_322t1:c.499C>T
LRG_322:g.13188C>T
LRG_322p1:p.Arg167Trp
NC_000003.11:g.10191506C>T
NM_000551.3:c.499C>T
NM_198156.2:c.376C>T
P40337:p.Arg167Trp
p.R167W
p.[Arg167Trp]

Protein change:

R126W; ARG167TRP

Links:

UniProtKB: P40337#VAR_005762; OMIM: 608537.0003; dbSNP: rs5030820

NCBI 1000 Genomes Browser:

rs5030820

Molecular consequence:

NM_001354723.2:c.*53C>T - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_000551.4:c.499C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_198156.3:c.376C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000211816	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (May 25, 2022)	germline	clinical testing	Citation Link,
SCV000805354	PreventionGenetics, part of Exact Sciences	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 12, 2018)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001473258	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process)	Pathogenic (Aug 3, 2020)	germline	clinical testing	Citation Link,
SCV002011308	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 3, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

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

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From GeneDx, SCV000211816.14

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

Published functional studies demonstrate a damaging effect: Variant does not bind to elongin B or elongin C, resulting in an unstable protein that is rapidly degraded by the proteasome (Schoenfeld 2000); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed at a significant frequency in large population cohorts (gnomAD); Also known as p.(R208W) and p.(R238W); This variant is associated with the following publications: (PMID: 28873162, 14973063, 10205047, 9156047, 21519372, 23512077, 18836774, 12000816, 25119015, 19602254, 10900011, 7987306, 25563310, 27539324, 27527340, 27682873, 28944243, 28094316, 9829912, 22799452, 9829911, 8956040, 29124493, 25390905, 16042317, 29616089, 30522901, 30042107, 20233476, 29625052, 33745191, 32561571, 31589614, 30787465, 34377882, 34439168, 33828526, 34036514)

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

From PreventionGenetics, part of Exact Sciences, SCV000805354.1

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

#	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

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV001473258.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

The VHL c.499C>T; p.Arg167Trp variant (rs5030820), also reported as p.Arg238Trp, is a common pathogenic variant in individuals and families affected with Von Hippel-Lindau syndrome (Crossey 1994, Fishbein 2013, Peng 2017, Wang 2018, Zhang 2015). This variant is reported in ClinVar (Variation ID: 2218), and is only observed on two alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The arginine at codon 167 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Functional analyses of the variant protein show loss of elongin binding leading to VHL protein degradation (Leonardi 2011, Ohh 1999, Peng 2017, Schoenfeld 2000). Additionally, other amino acid substitutions at this codon (Gln, Gly, Leu, Pro) have been reported in individuals with Von Hippel-Lindau syndrome and are considered pathogenic (Crossey 1994, Zhang 2015). Based on available information, this variant is considered to be pathogenic. References: Crossey PA et al. Identification of intragenic mutations in the von Hippel-Lindau disease tumour suppressor gene and correlation with disease phenotype. Hum Mol Genet. 1994;3(8):1303-1308. Fishbein L et al. Inherited mutations in pheochromocytoma and paraganglioma: why all patients should be offered genetic testing. Ann Surg Oncol. 2013;20(5):1444-1450. Leonardi E et al. Identification and in silico analysis of novel von Hippel-Lindau (VHL) gene variants from a large population. Ann Hum Genet. 2011;75(4):483-496. Ohh M et al. Synthetic peptides define critical contacts between elongin C, elongin B, and the von Hippel-Lindau protein. J Clin Invest. 1999;104(11):1583-1591. Peng S et al. Genotype-phenotype correlations in Chinese von Hippel-Lindau disease patients. Oncotarget. 2017;8(24):38456-38465. Schoenfeld AR et al. Elongin BC complex prevents degradation of von Hippel-Lindau tumor suppressor gene products. Proc Natl Acad Sci U S A. 2000;97(15):8507-8512. Wang Y et al. Pedigree analysis, diagnosis and treatment in Von Hippel-Lindau syndrome: A report of three cases. Oncol Lett. 2018;15(4):4882-4890. Zhang J et al. Clinical and genetic investigation of a multi-generational Chinese family afflicted with Von Hippel-Lindau disease. Chin Med J (Engl). 2015;128(1):32-38.

#	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

From Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden, SCV002011308.3

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

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

Last Updated: Oct 13, 2024

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