NM_000551.4(VHL):c.422dup (p.Asn141fs) AND multiple conditions

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Apr 1, 2016
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:: RCV000474557.6

Allele description [Variation Report for NM_000551.4(VHL):c.422dup (p.Asn141fs)]

NM_000551.4(VHL):c.422dup (p.Asn141fs)

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:

Duplication

Cytogenetic location:

3p25.3

Genomic location:

Preferred name:

NM_000551.4(VHL):c.422dup (p.Asn141fs)

Other names:

NM_000551.4(VHL):c.422dup; p.Asn141fs

HGVS:

NC_000003.12:g.10146595dup
NG_008212.3:g.9961dup
NG_046756.1:g.4357dup
NM_000551.4:c.422dupMANE SELECT
NM_001354723.2:c.*18-3192dup
NM_198156.3:c.341-3192dup
NP_000542.1:p.Asn141fs
LRG_322:g.9961dup
NC_000003.11:g.10188277_10188278insA
NC_000003.11:g.10188279dup
NM_000551.3:c.422dupA

Protein change:

N141fs

Links:

dbSNP: rs1553619976

NCBI 1000 Genomes Browser:

rs1553619976

Molecular consequence:

NM_000551.4:c.422dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354723.2:c.*18-3192dup - intron variant - [Sequence Ontology: SO:0001627]
NM_198156.3:c.341-3192dup - intron variant - [Sequence Ontology: SO:0001627]

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

Recent activity

Clear Turn Off Turn On

SFRP1 [Sphaerodactylus townsendi]
SFRP1 [Sphaerodactylus townsendi]
Gene ID:125441745

Gene

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000553408	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Apr 1, 2016)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 14987375, 10900011, 19280651, 8069305, 8707293, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000553408

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Apr 1, 2016)

germline

clinical testing

PubMed (6)
[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

Molecular pathology of von HippelLindau disease and the VHL tumour suppressor gene.

Richards FM.

Expert Rev Mol Med. 2001 Mar 19;2001:1-27. doi: 10.1017/S1462399401002654. No abstract available.

PubMed [citation]

PMID:: 14987375

Elongin BC complex prevents degradation of von Hippel-Lindau tumor suppressor gene products.

Schoenfeld AR, Davidowitz EJ, Burk RD.

Proc Natl Acad Sci U S A. 2000 Jul 18;97(15):8507-12.

PubMed [citation]

PMID:: 10900011
PMCID:: PMC26978

See all PubMed Citations (6)

Details of each submission

From Invitae, SCV000553408.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

This truncation deletes the VHL elongin binding domain encoded by exon 3 (PMID: 14987375). This domain is required for protein stability and tumor suppressive activity (PMID: 10900011). Deletions of exon 3 have been reported in multiple families with von Hippel-Landau Syndrome (PMID: 19280651, 8069305, 8707293). For these reasons, this variant has been classified as Pathogenic. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a VHL-related disease. This sequence change inserts 1 nucleotide in exon 2 of the VHL mRNA (c.422dupA), causing a frameshift at codon 141. This creates a premature translational stop signal within the last 15 amino acids of the penultimate exon of the VHL mRNA (p.Asn141Lysfs*3). While this is not anticipated to result in nonsense mediated decay, it is expected to result in a truncated VHL protein.

#	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: Aug 25, 2024

ClinVar

Relating variation to medicine