NM_000551.4(VHL):c.34G>T (p.Glu12Ter) AND Von Hippel-Lindau syndrome

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Jun 28, 2023
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:: RCV004007469.2

Allele description [Variation Report for NM_000551.4(VHL):c.34G>T (p.Glu12Ter)]

NM_000551.4(VHL):c.34G>T (p.Glu12Ter)

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.34G>T (p.Glu12Ter)

HGVS:

NC_000003.12:g.10141881G>T
NG_008212.3:g.5247G>T
NM_000551.4:c.34G>TMANE SELECT
NM_001354723.2:c.34G>T
NM_198156.3:c.34G>T
NP_000542.1:p.Glu12Ter
NP_000542.1:p.Glu12Ter
NP_001341652.1:p.Glu12Ter
NP_937799.1:p.Glu12Ter
LRG_322t1:c.34G>T
LRG_322:g.5247G>T
LRG_322p1:p.Glu12Ter
NC_000003.11:g.10183565G>T
NM_000551.3:c.34G>T
NR_176335.1:n.104G>T

Protein change:

E12*

Molecular consequence:

NM_000551.4:c.34G>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001354723.2:c.34G>T - nonsense - [Sequence Ontology: SO:0001587]
NM_198156.3:c.34G>T - nonsense - [Sequence Ontology: SO:0001587]

Observations:

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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RecName: Full=Ankyrin repeat and MYND domain-containing protein 2
RecName: Full=Ankyrin repeat and MYND domain-containing protein 2
gi|110832743|sp|Q3TPE9.1|ANKY2_MOUS

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004841629	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Jun 28, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 9671762, 9751722, 10102622, 23541568, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004841629

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Jun 28, 2023)

germline

clinical testing

PubMed (5)
[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	1	not provided	not provided	108544	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 (5)

Details of each submission

From All of Us Research Program, National Institutes of Health, SCV004841629.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (5)

Description

This variant changes 1 nucleotide in exon 1 of the VHL gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. However, VHL encodes a smaller protein isoform from internal translation initiation at methionine 54 (PMID: 9671762, 10102622). Functional studies have reported that the smaller protein isoform can rescue VHL functions in renal carcinoma cells lacking endogenous VHL expression (PMID: 9671762, 9751722, 10102622) and a mouse model for VHL start codon loss found that most VHL functions are intact (PMID: 23541568). This nonsense mutation, c.34G>T (p.Glu12*) is not expected to disrupt the expression of the smaller functional isoform. To our knowledge, this variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/31378 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of VHL function is a known mechanism of disease (clinicalgenome.org). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	108544	not provided	not provided		1	not provided	not provided	not provided

Last Updated: May 7, 2024

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