NM_000551.4(VHL):c.16G>T (p.Glu6Ter) AND multiple conditions

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Mar 9, 2020
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:: RCV001369118.6

Allele description [Variation Report for NM_000551.4(VHL):c.16G>T (p.Glu6Ter)]

NM_000551.4(VHL):c.16G>T (p.Glu6Ter)

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.16G>T (p.Glu6Ter)

HGVS:

NC_000003.12:g.10141863G>T
NG_008212.3:g.5229G>T
NM_000551.4:c.16G>TMANE SELECT
NM_001354723.2:c.16G>T
NM_198156.3:c.16G>T
NP_000542.1:p.Glu6Ter
NP_001341652.1:p.Glu6Ter
NP_937799.1:p.Glu6Ter
LRG_322:g.5229G>T
NC_000003.11:g.10183547G>T

Protein change:

E6*

Links:

dbSNP: rs545406510

NCBI 1000 Genomes Browser:

rs545406510

Molecular consequence:

NM_000551.4:c.16G>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001354723.2:c.16G>T - nonsense - [Sequence Ontology: SO:0001587]
NM_198156.3:c.16G>T - nonsense - [Sequence Ontology: SO:0001587]

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

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
SCV001565548	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Mar 9, 2020)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 9671762, 9751722, 10102622, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001565548

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Mar 9, 2020)

germline

clinical testing

PubMed (4)
[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

A second major native von Hippel-Lindau gene product, initiated from an internal translation start site, functions as a tumor suppressor.

Schoenfeld A, Davidowitz EJ, Burk RD.

Proc Natl Acad Sci U S A. 1998 Jul 21;95(15):8817-22.

PubMed [citation]

PMID:: 9671762
PMCID:: PMC21160

pVHL19 is a biologically active product of the von Hippel-Lindau gene arising from internal translation initiation.

Iliopoulos O, Ohh M, Kaelin WG Jr.

Proc Natl Acad Sci U S A. 1998 Sep 29;95(20):11661-6.

PubMed [citation]

PMID:: 9751722
PMCID:: PMC21697

See all PubMed Citations (4)

Details of each submission

From Invitae, SCV001565548.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

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. Downstream of the known ATG start site, the nearest methionine codon that can be used to initiate translation of the VHL protein lies at codon 54. Several studies have shown that the VHL protein created from this downstream methionine is biologically active, and exhibits properties similar to the full-length, wild-type protein (PMID: 9671762, 9751722, 10102622). Based on these results, the impact of this variant on VHL protein function is uncertain. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This sequence change results in a premature translational stop signal in the VHL gene (p.Glu6*). It is unclear whether it will result in an absent or disrupted protein product because a highly conserved, in-frame methionine located at codon 54 has the potential to rescue this truncating variant.

#	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: May 1, 2024

ClinVar

Relating variation to medicine