NM_000551.4(VHL):c.245G>T (p.Arg82Leu) AND multiple conditions

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Aug 17, 2019
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:: RCV000631271.10

Allele description [Variation Report for NM_000551.4(VHL):c.245G>T (p.Arg82Leu)]

NM_000551.4(VHL):c.245G>T (p.Arg82Leu)

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.245G>T (p.Arg82Leu)

HGVS:

NC_000003.12:g.10142092G>T
NG_008212.3:g.5458G>T
NM_000551.4:c.245G>TMANE SELECT
NM_001354723.2:c.245G>T
NM_198156.3:c.245G>T
NP_000542.1:p.Arg82Leu
NP_000542.1:p.Arg82Leu
NP_001341652.1:p.Arg82Leu
NP_937799.1:p.Arg82Leu
LRG_322t1:c.245G>T
LRG_322:g.5458G>T
LRG_322p1:p.Arg82Leu
NC_000003.11:g.10183776G>T
NM_000551.3:c.245G>T

Protein change:

R82L

Links:

dbSNP: rs794726890

NCBI 1000 Genomes Browser:

rs794726890

Molecular consequence:

NM_000551.4:c.245G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354723.2:c.245G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_198156.3:c.245G>T - 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
SCV000752299	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Aug 17, 2019)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 12603429, 20447124, 26973240, 11739384, 10823831, 23327821, 23626751, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000752299

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Aug 17, 2019)

germline

clinical testing

PubMed (8)
[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

A type 2B von Hippel-Lindau family masquerading as a metastatic sporadic renal cell carcinoma.

André T, Bossard C, Gattegno B, Plouin PF, Benoit G, Richard S.

BJU Int. 2003 Mar;91(4):425-6. No abstract available.

PubMed [citation]

PMID:: 12603429

Clinical and molecular features of familial and sporadic cases of von Hippel-Lindau disease from Mexico.

Chacon-Camacho OF, Rodriguez-Dennen F, Camacho-Molina A, Rasmussen A, Alonso-Vilatela E, Zenteno JC.

Clin Exp Ophthalmol. 2010 Apr;38(3):277-83. doi: 10.1111/j.1442-9071.2010.02241.x.

PubMed [citation]

PMID:: 20447124

See all PubMed Citations (8)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000752299.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

For these reasons, this variant has been classified as Pathogenic. A different missense substitution at this codon (p.Arg82Pro) has been reported to segregate with¬†von Hippel-Lindau syndrome in two families (PMID: 12603429, 20447124). Experimental studies have shown that this missense change disrupts the normal function of VHL protein (PMID: 26973240, 11739384, 10823831). This suggests that the arginine residue is critical for VHL protein function and that other missense substitutions at this position may also be pathogenic. This variant has been reported to be de novo in an individual affected with bilateral adrenal pheochromocytoma (PMID: 23327821). In addition, this variant has been reported to segregate with bilateral pheochromocytoma in one family (PMID: 23626751). This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with leucine at codon 82 of the VHL protein (p.Arg82Leu). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and leucine.

#	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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