NM_000551.4(VHL):c.430G>A (p.Gly144Arg) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Mar 26, 2024
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:: RCV002332473.3

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

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

HGVS:

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

Protein change:

G144R

Links:

dbSNP: rs869025650

NCBI 1000 Genomes Browser:

rs869025650

Molecular consequence:

NM_001354723.2:c.*18-3184G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_198156.3:c.341-3184G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_000551.4:c.430G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Hereditary cancer-predisposing syndrome
Synonyms:: Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002627580	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Mar 26, 2024)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 15921386, 21449869, 24115288, 29891534, 31383958 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002627580

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Mar 26, 2024)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

Citation Link

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

An elusive phaeochromocytoma.

Yates CJ, McAuley SA, Grodski S, Hamblin PS, Ebeling PR.

Med J Aust. 2011 Jan 3;194(1):44-5. No abstract available.

PubMed [citation]

PMID:: 21449869

See all PubMed Citations (5)

Details of each submission

From Ambry Genetics, SCV002627580.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

The p.G144R variant (also known as c.430G>A), located in coding exon 2 of the VHL gene, results from a G to A substitution at nucleotide position 430. The glycine at codon 144 is replaced by arginine, an amino acid with dissimilar properties. This alteration has been reported in an individual with a pheochromocytoma and in an individual with a paraganglioma (Yates CJ et al. Med J Aust, 2011 Jan;194:44-5; Favier J et al. Mod Pathol, 2020 01;33:57-64). It has also been reported in individuals affected with polycythemia and erythrocytosis, in the heterozygous state (Randi ML et al. Haematologica, 2005 May;90:689-91), and in conjunction with a second alteration in VHL (Bento C et al. Hum Mutat, 2014 Jan;35:15-26; Lenglet M et al. Blood, 2018 08;132:469-483). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

#	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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