NM_000551.4(VHL):c.462A>G (p.Pro154=) AND multiple conditions

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Nov 7, 2018
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:: RCV000474447.11

Allele description [Variation Report for NM_000551.4(VHL):c.462A>G (p.Pro154=)]

NM_000551.4(VHL):c.462A>G (p.Pro154=)

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.462A>G (p.Pro154=)

Other names:

NP_000542.1:p.P154P

HGVS:

NC_000003.12:g.10146635A>G
NG_008212.3:g.10001A>G
NG_046756.1:g.4397A>G
NM_000551.4:c.462A>GMANE SELECT
NM_001354723.2:c.*18-3152A>G
NM_198156.3:c.341-3152A>G
NP_000542.1:p.Pro154=
NP_000542.1:p.Pro154=
LRG_322t1:c.462A>G
LRG_322:g.10001A>G
LRG_322p1:p.Pro154=
NC_000003.11:g.10188319A>G
NM_000551.3:c.462A>G

Links:

dbSNP: rs1060503562

NCBI 1000 Genomes Browser:

rs1060503562

Molecular consequence:

NM_001354723.2:c.*18-3152A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_198156.3:c.341-3152A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_000551.4:c.462A>G - synonymous variant - [Sequence Ontology: SO:0001819]

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
SCV000553406	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Nov 7, 2018)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 9829912, 17006605, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000553406

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Nov 7, 2018)

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

Germline mutation profile of the VHL gene in von Hippel-Lindau disease and in sporadic hemangioblastoma.

Olschwang S, Richard S, Boisson C, Giraud S, Laurent-Puig P, Resche F, Thomas G.

Hum Mutat. 1998;12(6):424-30.

PubMed [citation]

PMID:: 9829912

Molecular analysis of two uncharacterized sequence variants of the VHL gene.

Martella M, Salviati L, Casarin A, Trevisson E, Opocher G, Polli R, Gross D, Murgia A.

J Hum Genet. 2006;51(11):964-968. doi: 10.1007/s10038-006-0054-9. Epub 2006 Sep 28.

PubMed [citation]

PMID:: 17006605

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000553406.7

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

Description

This variant has not been reported in the literature in individuals with VHL-related disease.¬† ClinVar contains an entry for this variant (Variation ID: 411977). This variant is not present in population databases (ExAC no frequency). This sequence change affects codon 154 of the VHL mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the VHL protein. 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. A different variant (c.462A>C) affecting this nucleotide with the same silent change has been reported to segregate with disease in families affected with von Hippel-Lindau syndrome (PMID: 9829912, 17006605), and experimental studies suggest that this nucleotide may be crucial for normal mRNA splicing (PMID: 17006605). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies.

#	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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