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NM_000551.4(VHL):c.464-2A>G AND VHL-related disorder

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Jul 15, 2024
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
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:
RCV004725066.1

Allele description [Variation Report for NM_000551.4(VHL):c.464-2A>G]

NM_000551.4(VHL):c.464-2A>G

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.464-2A>G
HGVS:
  • NC_000003.12:g.10149785A>G
  • NG_008212.3:g.13151A>G
  • NG_046756.1:g.7547A>G
  • NM_000551.4:c.464-2A>GMANE SELECT
  • NM_001354723.2:c.*18-2A>G
  • NM_198156.3:c.341-2A>G
  • LRG_322t1:c.464-2A>G
  • LRG_322:g.13151A>G
  • NC_000003.11:g.10191469A>G
  • NM_000551.3:c.464-2A>G
Links:
dbSNP: rs5030816
NCBI 1000 Genomes Browser:
rs5030816
Molecular consequence:
  • NM_000551.4:c.464-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001354723.2:c.*18-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_198156.3:c.341-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
Functional consequence:
sequence_variant_affecting_splicing [Sequence Ontology: SO:1000071] - Comment(s)

Condition(s)

Name:
VHL-related disorder
Synonyms:
VHL-related condition
Identifiers:

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV005335365PreventionGenetics, part of Exact Sciences
no assertion criteria provided
Pathogenic
(Jul 15, 2024) 		germlineclinical testing

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Details of each submission

From PreventionGenetics, part of Exact Sciences, SCV005335365.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

The VHL c.464-2A>G variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. This variant, described as 677-2A>G, has been reported to occur de novo in an individual with Von Hippel-Lindau syndrome (Glavac et al. 1996. PubMed ID: 8707293). This variant has also been reported in other individuals with VHL-related disease phenotypes (Liu et al. 2020. PubMed ID: 33004005; Reich et al. 2021. PubMed ID: 33720516; Hama et al. 2023. PubMed ID: 37020505; Krauss et al. 2018. PubMed ID: 29748190). Alternate nucleotide changes at the same genomic position (c.464-2A>C, c.464-2A>T) have been reported in individuals with VHL-associated disease (Whaley et al. 1994. PubMed ID: 7977367; described as 677-2A>T, Glavac et al 1996. PubMed ID: 8707293). This variant has not been reported in a large population database, indicating this variant is rare. It is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/223222/). Variants that disrupt the consensus splice acceptor site in VHL are expected to be pathogenic. This variant is interpreted as pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Nov 3, 2024