NM_000551.4(VHL):c.533_534del (p.Leu178fs) AND multiple conditions

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Mar 26, 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:: RCV002536594.3

Allele description [Variation Report for NM_000551.4(VHL):c.533_534del (p.Leu178fs)]

NM_000551.4(VHL):c.533_534del (p.Leu178fs)

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.533_534del (p.Leu178fs)

HGVS:

NC_000003.12:g.10149856_10149857del
NG_008212.3:g.13222_13223del
NG_046756.1:g.7618_7619del
NM_000551.4:c.533_534delMANE SELECT
NM_001354723.2:c.*87_*88del
NM_198156.3:c.410_411del
NP_000542.1:p.Leu178fs
NP_937799.1:p.Leu137fs
LRG_322:g.13222_13223del
NC_000003.11:g.10191540_10191541del
NM_000551.3:c.533_534delTG

Protein change:

L137fs

Links:

dbSNP: rs1559429736

NCBI 1000 Genomes Browser:

rs1559429736

Molecular consequence:

NM_001354723.2:c.*87_*88del - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_000551.4:c.533_534del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_198156.3:c.410_411del - frameshift variant - [Sequence Ontology: SO:0001589]

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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV003220439	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Mar 26, 2023)	germline	clinical testing	PubMed (11) [See all records that cite these PMIDs] 7563486, 7987306, 8707293, 8772572, 10567493, 11309459, 11331612, 16452184, 18567581, 23772956, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003220439

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Mar 26, 2023)

germline

clinical testing

PubMed (11)
[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

Consequences of direct genetic testing for germline mutations in the clinical management of families with multiple endocrine neoplasia, type II.

Neumann HP, Eng C, Mulligan LM, Glavac D, Zäuner I, Ponder BA, Crossey PA, Maher ER, Brauch H.

JAMA. 1995 Oct 11;274(14):1149-51.

PubMed [citation]

PMID:: 7563486

Identification of intragenic mutations in the von Hippel-Lindau disease tumour suppressor gene and correlation with disease phenotype.

Crossey PA, Richards FM, Foster K, Green JS, Prowse A, Latif F, Lerman MI, Zbar B, Affara NA, Ferguson-Smith MA, et al.

Hum Mol Genet. 1994 Aug;3(8):1303-8.

PubMed [citation]

PMID:: 7987306

See all PubMed Citations (11)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003220439.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (11)

Description

For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the VHL protein in which other variant(s) (p.Ser183*) have been determined to be pathogenic (PMID: 7563486, 7987306, 8707293, 8772572, 10567493, 11309459, 11331612, 16452184, 18567581, 23772956; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 625259). This variant has not been reported in the literature in individuals affected with VHL-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change results in a frameshift in the VHL gene (p.Leu178Argfs*77). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 36 amino acid(s) of the VHL protein and extend the protein by 40 additional amino acid residues.

#	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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