NM_000551.4(VHL):c.487C>T (p.Leu163Phe) AND multiple conditions

Germline classification:: Pathogenic (1 submission)
Last evaluated:: May 15, 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:: RCV001224534.7

Allele description [Variation Report for NM_000551.4(VHL):c.487C>T (p.Leu163Phe)]

NM_000551.4(VHL):c.487C>T (p.Leu163Phe)

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.487C>T (p.Leu163Phe)

HGVS:

NC_000003.12:g.10149810C>T
NG_008212.3:g.13176C>T
NG_046756.1:g.7572C>T
NM_000551.4:c.487C>TMANE SELECT
NM_001354723.2:c.*41C>T
NM_198156.3:c.364C>T
NP_000542.1:p.Leu163Phe
NP_000542.1:p.Leu163Phe
NP_937799.1:p.Leu122Phe
LRG_322t1:c.487C>T
LRG_322:g.13176C>T
LRG_322p1:p.Leu163Phe
NC_000003.11:g.10191494C>T
NM_000551.3:c.487C>T

Protein change:

L122F

Links:

dbSNP: rs1553620318

NCBI 1000 Genomes Browser:

rs1553620318

Molecular consequence:

NM_001354723.2:c.*41C>T - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_000551.4:c.487C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_198156.3:c.364C>T - 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
SCV001396738	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (May 15, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 11986208, 19270817, 29124493, 32671223, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001396738

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(May 15, 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	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Paraneoplastic erythrocytosis associated with an inactivating point mutation of the von Hippel-Lindau gene in a renal cell carcinoma.

Wiesener MS, Seyfarth M, Warnecke C, Jürgensen JS, Rosenberger C, Morgan NV, Maher ER, Frei U, Eckardt KU.

Blood. 2002 May 15;99(10):3562-5.

PubMed [citation]

PMID:: 11986208

Improved detection of germline mutations in Korean VHL patients by multiple ligation-dependent probe amplification analysis.

Cho HJ, Ki CS, Kim JW.

J Korean Med Sci. 2009 Feb;24(1):77-83. doi: 10.3346/jkms.2009.24.1.77. Epub 2009 Feb 28.

PubMed [citation]

PMID:: 19270817
PMCID:: PMC2650969

See all PubMed Citations (5)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001396738.5

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

Description

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Leu163 amino acid residue in VHL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11986208, 19270817; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 480772). This variant is also known as 700C>T. This missense change has been observed in individuals with von Hippel-Lindau syndrome (PMID: 29124493, 32671223; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 163 of the VHL protein (p.Leu163Phe).

#	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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