NM_000551.4(VHL):c.236G>T (p.Arg79Leu) AND multiple conditions

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Jan 3, 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:: RCV002962871.3

Allele description [Variation Report for NM_000551.4(VHL):c.236G>T (p.Arg79Leu)]

NM_000551.4(VHL):c.236G>T (p.Arg79Leu)

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.236G>T (p.Arg79Leu)

HGVS:

NC_000003.12:g.10142083G>T
NG_008212.3:g.5449G>T
NM_000551.4:c.236G>TMANE SELECT
NM_001354723.2:c.236G>T
NM_198156.3:c.236G>T
NP_000542.1:p.Arg79Leu
NP_000542.1:p.Arg79Leu
NP_001341652.1:p.Arg79Leu
NP_937799.1:p.Arg79Leu
LRG_322t1:c.236G>T
LRG_322:g.5449G>T
LRG_322p1:p.Arg79Leu
NC_000003.11:g.10183767G>T
NM_000551.3:c.236G>T
NR_176335.1:n.306G>T

Protein change:

R79L

Molecular consequence:

NM_000551.4:c.236G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354723.2:c.236G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_198156.3:c.236G>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
SCV003285269	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 3, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 15642680, 24555745, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003285269

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jan 3, 2022)

germline

clinical testing

PubMed (3)
[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

Congenital polycythemia with homozygous and heterozygous mutations of von Hippel-Lindau gene: five new Caucasian patients.

Bento MC, Chang KT, Guan Y, Liu E, Caldas G, Gatti RA, Prchal JT.

Haematologica. 2005 Jan;90(1):128-9.

PubMed [citation]

PMID:: 15642680

Genotype-phenotype correlations, and retinal function and structure in von Hippel-Lindau disease.

Wittström E, Nordling M, Andréasson S.

Ophthalmic Genet. 2014 Jun;35(2):91-106. doi: 10.3109/13816810.2014.886265. Epub 2014 Feb 20.

PubMed [citation]

PMID:: 24555745

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003285269.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

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. This variant disrupts the p.Arg79 amino acid residue in VHL. Other variant(s) that disrupt this residue have been observed in individuals with VHL-related conditions (PMID: 15642680, 24555745), which suggests that this may be a clinically significant amino acid residue. 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. This variant has not been reported in the literature in individuals affected with VHL-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 79 of the VHL protein (p.Arg79Leu).

#	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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