NM_000551.4(VHL):c.250G>C (p.Val84Leu) AND multiple conditions

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Mar 26, 2023
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:: RCV001382229.7

Allele description [Variation Report for NM_000551.4(VHL):c.250G>C (p.Val84Leu)]

NM_000551.4(VHL):c.250G>C (p.Val84Leu)

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.250G>C (p.Val84Leu)

HGVS:

NC_000003.12:g.10142097G>C
NG_008212.3:g.5463G>C
NM_000551.4:c.250G>CMANE SELECT
NM_001354723.2:c.250G>C
NM_198156.3:c.250G>C
NP_000542.1:p.Val84Leu
NP_000542.1:p.Val84Leu
NP_001341652.1:p.Val84Leu
NP_937799.1:p.Val84Leu
LRG_322t1:c.250G>C
LRG_322:g.5463G>C
LRG_322p1:p.Val84Leu
NC_000003.11:g.10183781G>C
NM_000551.3:c.250G>C
P40337:p.Val84Leu

Protein change:

V84L

Links:

UniProtKB: P40337#VAR_005692; dbSNP: rs5030827

NCBI 1000 Genomes Browser:

rs5030827

Molecular consequence:

NM_000551.4:c.250G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354723.2:c.250G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_198156.3:c.250G>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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Homo sapiens protein kinase cAMP-dependent type I regulatory subunit beta (PRKAR...
Homo sapiens protein kinase cAMP-dependent type I regulatory subunit beta (PRKAR1B), transcript variant 2, mRNA
gi|1890261483|ref|NM_002735.3|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001580901	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Mar 26, 2023)	germline	clinical testing	PubMed (13) [See all records that cite these PMIDs] 11331612, 11331613, 12510195, 19228690, 19602254, 21791076, 8592333, 11409863, 16502427, 19215943, 19270817, 25078357, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001580901

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Mar 26, 2023)

germline

clinical testing

PubMed (13)
[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

von Hippel-Lindau protein mutants linked to type 2C VHL disease preserve the ability to downregulate HIF.

Hoffman MA, Ohh M, Yang H, Klco JM, Ivan M, Kaelin WG Jr.

Hum Mol Genet. 2001 May 1;10(10):1019-27.

PubMed [citation]

PMID:: 11331612

Contrasting effects on HIF-1alpha regulation by disease-causing pVHL mutations correlate with patterns of tumourigenesis in von Hippel-Lindau disease.

Clifford SC, Cockman ME, Smallwood AC, Mole DR, Woodward ER, Maxwell PH, Ratcliffe PJ, Maher ER.

Hum Mol Genet. 2001 May 1;10(10):1029-38. Erratum in: Hum Mol Genet. 2021 May 28;30(9):844-845. doi: 10.1093/hmg/ddab037.

PubMed [citation]

PMID:: 11331613

See all PubMed Citations (13)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001580901.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (13)

Description

For these reasons, this variant has been classified as Pathogenic. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on VHL function (PMID: 11331612, 11331613, 12510195, 19228690, 19602254, 21791076). 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. ClinVar contains an entry for this variant (Variation ID: 229860). This missense change has been observed in individual(s) with von Hippel-Lindau syndrome (PMID: 8592333, 11409863, 16502427, 19215943, 19270817, 25078357). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 84 of the VHL protein (p.Val84Leu).

#	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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