NM_000551.4(VHL):c.448_449del (p.Asn150fs) AND multiple conditions

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Apr 4, 2022
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:: RCV001061553.6

Allele description [Variation Report for NM_000551.4(VHL):c.448_449del (p.Asn150fs)]

NM_000551.4(VHL):c.448_449del (p.Asn150fs)

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.448_449del (p.Asn150fs)

HGVS:

NC_000003.12:g.10146621_10146622del
NG_008212.3:g.9987_9988del
NG_046756.1:g.4383_4384del
NM_000551.4:c.448_449delMANE SELECT
NM_001354723.2:c.*18-3166_*18-3165del
NM_198156.3:c.341-3166_341-3165del
NP_000542.1:p.Asn150fs
LRG_322t1:c.448_449del
LRG_322:g.9987_9988del
NC_000003.11:g.10188305_10188306del
NM_000551.3:c.448_449del

Protein change:

N150fs

Links:

dbSNP: rs1696266605

NCBI 1000 Genomes Browser:

rs1696266605

Molecular consequence:

NM_000551.4:c.448_449del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354723.2:c.*18-3166_*18-3165del - intron variant - [Sequence Ontology: SO:0001627]
NM_198156.3:c.341-3166_341-3165del - 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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001226299	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Apr 4, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 8707293, 10567493, 11309459, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001226299

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Apr 4, 2022)

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

Mutations in the VHL tumor suppressor gene and associated lesions in families with von Hippel-Lindau disease from central Europe.

Glavac D, Neumann HP, Wittke C, Jaenig H, Masek O, Streicher T, Pausch F, Engelhardt D, Plate KH, Höfler H, Chen F, Zbar B, Brauch H.

Hum Genet. 1996 Sep;98(3):271-80.

PubMed [citation]

PMID:: 8707293

The impact of molecular genetic analysis of the VHL gene in patients with haemangioblastomas of the central nervous system.

Gläsker S, Bender BU, Apel TW, Natt E, van Velthoven V, Scheremet R, Zentner J, Neumann HP.

J Neurol Neurosurg Psychiatry. 1999 Dec;67(6):758-62.

PubMed [citation]

PMID:: 10567493
PMCID:: PMC1736691

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001226299.5

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

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: 8707293, 10567493, 11309459). 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: 856153). 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 creates a premature translational stop signal (p.Asn150Tyrfs*23) in the VHL gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 64 amino acid(s) of the 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: Sep 29, 2024

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