NM_000551.4(VHL):c.430G>C (p.Gly144Arg) AND multiple conditions

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Aug 17, 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:: RCV000631288.6

Allele description [Variation Report for NM_000551.4(VHL):c.430G>C (p.Gly144Arg)]

NM_000551.4(VHL):c.430G>C (p.Gly144Arg)

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.430G>C (p.Gly144Arg)

HGVS:

NC_000003.12:g.10146603G>C
NG_008212.3:g.9969G>C
NG_046756.1:g.4365G>C
NM_000551.4:c.430G>CMANE SELECT
NM_001354723.2:c.*18-3184G>C
NM_198156.3:c.341-3184G>C
NP_000542.1:p.Gly144Arg
NP_000542.1:p.Gly144Arg
LRG_322t1:c.430G>C
LRG_322:g.9969G>C
LRG_322p1:p.Gly144Arg
NC_000003.11:g.10188287G>C
NM_000551.3:c.430G>C

Protein change:

G144R

Links:

dbSNP: rs869025650

NCBI 1000 Genomes Browser:

rs869025650

Molecular consequence:

NM_001354723.2:c.*18-3184G>C - intron variant - [Sequence Ontology: SO:0001627]
NM_198156.3:c.341-3184G>C - intron variant - [Sequence Ontology: SO:0001627]
NM_000551.4:c.430G>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
SCV000752316	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Aug 17, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 15921386, 24115288, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000752316

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Aug 17, 2023)

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

Low frequency of VHL gene mutations in young individuals with polycythemia and high serum erythropoietin.

Randi ML, Murgia A, Putti MC, Martella M, Casarin A, Opocher G, Fabris F.

Haematologica. 2005 May;90(5):689-91.

PubMed [citation]

PMID:: 15921386

Genetic basis of congenital erythrocytosis: mutation update and online databases.

Bento C, Percy MJ, Gardie B, Maia TM, van Wijk R, Perrotta S, Della Ragione F, Almeida H, Rossi C, Girodon F, Aström M, Neumann D, Schnittger S, Landin B, Minkov M, Randi ML, Richard S, Casadevall N, Vainchenker W, Rives S, Hermouet S, Ribeiro ML, et al.

Hum Mutat. 2014 Jan;35(1):15-26. doi: 10.1002/humu.22448. Epub 2013 Oct 22.

PubMed [citation]

PMID:: 24115288

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000752316.3

#	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. 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: 526689). This missense change has been observed in individual(s) with polycythemia and congenital erythrocytosis (PMID: 15921386, 24115288). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 144 of the VHL protein (p.Gly144Arg).

#	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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