NM_000551.4(VHL):c.377del (p.Asp126fs) AND Von Hippel-Lindau syndrome

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jul 3, 2017
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:: RCV000528640.2

Allele description [Variation Report for NM_000551.4(VHL):c.377del (p.Asp126fs)]

NM_000551.4(VHL):c.377del (p.Asp126fs)

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:

Deletion

Cytogenetic location:

3p25.3

Genomic location:

Preferred name:

NM_000551.4(VHL):c.377del (p.Asp126fs)

HGVS:

NC_000003.12:g.10146550del
NG_008212.3:g.9916del
NG_046756.1:g.4312del
NM_000551.4:c.377delMANE SELECT
NM_001354723.2:c.*18-3237del
NM_198156.3:c.341-3237del
NP_000542.1:p.Asp126fs
LRG_322:g.9916del
NC_000003.11:g.10188234del
NC_000003.11:g.10188234delA
NM_000551.3:c.377delA

Protein change:

D126fs

Links:

dbSNP: rs1553619952

NCBI 1000 Genomes Browser:

rs1553619952

Molecular consequence:

NM_000551.4:c.377del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354723.2:c.*18-3237del - intron variant - [Sequence Ontology: SO:0001627]
NM_198156.3:c.341-3237del - intron variant - [Sequence Ontology: SO:0001627]

Condition(s)

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
SCV000626874	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jul 3, 2017)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000626874

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jul 3, 2017)

germline

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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000626874.1

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

Description

This sequence change results in a premature translational stop signal in the VHL gene (p.Asp126Valfs*33). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 88 amino acids of the VHL protein. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with VHL-related disease. This truncation disrupts a significant portion of the VHL elongin C binding domain (PMID: 14987375), which is required for protein stability and tumor suppressive activity (PMID: 10900011). Different truncations downstream of this variant (p.Asn141Lysfs*3, p.161Arg*, deletion of exon 3) have been determined to be pathogenic (PMID: 19270817, 10567493, 7987306, 12114495, 25867206, 15300849, 9829911, 9829912, 9452032, 8956040, 21362373, 18446368, 24301059, Invitae). This suggests that deletion of this region of the VHL protein is causative of disease. For these reasons, this variant has been classified as Pathogenic.

#	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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