NM_000551.4(VHL):c.463+8C>T AND not specified

Germline classification:: Conflicting interpretations of pathogenicity (5 submissions)
Last evaluated:: Jul 31, 2024
Review status:: criteria provided, conflicting classifications

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:: RCV000115747.30

Allele description [Variation Report for NM_000551.4(VHL):c.463+8C>T]

NM_000551.4(VHL):c.463+8C>T

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.463+8C>T

Other names:

IVS2+8C>T

HGVS:

NC_000003.12:g.10146644C>T
NG_008212.3:g.10010C>T
NG_046756.1:g.4406C>T
NM_000551.4:c.463+8C>TMANE SELECT
NM_001354723.2:c.*18-3143C>T
NM_198156.3:c.341-3143C>T
LRG_322t1:c.463+8C>T
LRG_322:g.10010C>T
NC_000003.11:g.10188328C>T
NM_000551.2:c.463+8C>T
NM_000551.3:c.463+8C>T

Links:

dbSNP: rs5030834

NCBI 1000 Genomes Browser:

rs5030834

Molecular consequence:

NM_000551.4:c.463+8C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001354723.2:c.*18-3143C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_198156.3:c.341-3143C>T - intron variant - [Sequence Ontology: SO:0001627]

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000149656	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Likely benign (Nov 1, 2017)	germline	clinical testing	Citation Link,
SCV000540656	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Likely benign (Mar 28, 2016)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002070985	Genetic Services Laboratory, University of Chicago	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely benign (Aug 6, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002552404	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jul 31, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004221483	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	benign (Mar 30, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

A systematic approach to assessing the clinical significance of genetic variants.

Duzkale H, Shen J, McLaughlin H, Alfares A, Kelly MA, Pugh TJ, Funke BH, Rehm HL, Lebo MS.

Clin Genet. 2013 Nov;84(5):453-63. doi: 10.1111/cge.12257.

PubMed [citation]

PMID:: 24033266
PMCID:: PMC3995020

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

See all PubMed Citations (3)

Details of each submission

From GeneDx, SCV000149656.11

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000540656.1

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

Description

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Outside splice consensus; 2 pubs in HGMD describe 1 proband with no segs

#	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

From Genetic Services Laboratory, University of Chicago, SCV002070985.1

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, SCV002552404.7

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

#	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

From Quest Diagnostics Nichols Institute San Juan Capistrano, SCV004221483.2

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

Description

The frequency of this variant in the general population (http://gnomad.broadinstitute.org) is higher than would generally be expected for pathogenic variants in this gene. Computational tools yielded predictions that this variant is unlikely to have an effect on normal RNA splicing. This nucleotide position exhibits low evolutionary conservation.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Nov 3, 2024

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