NM_000551.4(VHL):c.506T>C (p.Leu169Pro) AND multiple conditions

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Nov 1, 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:: RCV003766762.2

Allele description [Variation Report for NM_000551.4(VHL):c.506T>C (p.Leu169Pro)]

NM_000551.4(VHL):c.506T>C (p.Leu169Pro)

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:

single nucleotide variant

Cytogenetic location:

3p25.3

Genomic location:

Preferred name:

NM_000551.4(VHL):c.506T>C (p.Leu169Pro)

HGVS:

NC_000003.12:g.10149829T>C
NG_008212.3:g.13195T>C
NG_046756.1:g.7591T>C
NM_000551.4:c.506T>CMANE SELECT
NM_001354723.2:c.*60T>C
NM_198156.3:c.383T>C
NP_000542.1:p.Leu169Pro
NP_000542.1:p.Leu169Pro
NP_937799.1:p.Leu128Pro
LRG_322t1:c.506T>C
LRG_322:g.13195T>C
LRG_322p1:p.Leu169Pro
NC_000003.11:g.10191513T>C
NM_000551.3:c.506T>C

Protein change:

L128P

Links:

dbSNP: rs1131690962

NCBI 1000 Genomes Browser:

rs1131690962

Molecular consequence:

NM_001354723.2:c.*60T>C - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_000551.4:c.506T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_198156.3:c.383T>C - missense variant - [Sequence Ontology: SO:0001583]

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
SCV004569511	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Nov 1, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 11505222, 16809612, 17024664, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004569511

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Nov 1, 2023)

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

Association of GSTT1 non-null and NAT1 slow/rapid genotypes with von Hippel-Lindau tumour suppressor gene transversions in sporadic renal cell carcinoma.

Gallou C, Longuemaux S, Deloménie C, Méjean A, Martin N, Martinet S, Palais G, Bouvier R, Droz D, Krishnamoorthy R, Junien C, Béroud C, Dupret JM.

Pharmacogenetics. 2001 Aug;11(6):521-35.

PubMed [citation]

PMID:: 11505222

Neutrophils from patients with heterozygous germline mutations in the von Hippel Lindau protein (pVHL) display delayed apoptosis and enhanced bacterial phagocytosis.

Walmsley SR, Cowburn AS, Clatworthy MR, Morrell NW, Roper EC, Singleton V, Maxwell P, Whyte MK, Chilvers ER.

Blood. 2006 Nov 1;108(9):3176-8. Epub 2006 Jun 29.

PubMed [citation]

PMID:: 16809612

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004569511.1

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

Description

This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 169 of the VHL protein (p.Leu169Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with VHL-related conditions (PMID: 11505222, 16809612, 17024664). This variant is also known as c.719T>C. ClinVar contains an entry for this variant (Variation ID: 428809). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt VHL protein function with a positive predictive value of 95%. 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.

#	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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