NM_000551.4(VHL):c.487C>T (p.Leu163Phe) AND Hereditary cancer-predisposing syndrome

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Feb 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:: RCV000561095.5

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:: Hereditary cancer-predisposing syndrome
Synonyms:: Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000664462	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely pathogenic (Feb 15, 2023)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 15607616, 17102088, 19270817, 23102223, 27539324, 27811160, 29124493, 32671223 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000664462

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely pathogenic
(Feb 15, 2023)

germline

clinical testing

PubMed (8)
[See all records that cite these PMIDs]

Citation Link

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

Familial isolated pheochromocytoma presenting a new mutation in the von Hippel-Lindau gene.

Sansó G, Rudaz MC, Levin G, Barontini M.

Am J Hypertens. 2004 Dec;17(12 Pt 1):1107-11.

PubMed [citation]

PMID:: 15607616

von Hippel-Lindau gene mutation in non-syndromic familial pheochromocytomas.

Tong AL, Zeng ZP, Li HZ, Yang D, Lu L, Li M, Zhou YR, Zhang J, Chen S, Liang W.

Ann N Y Acad Sci. 2006 Aug;1073:203-7.

PubMed [citation]

PMID:: 17102088

See all PubMed Citations (8)

Details of each submission

From Ambry Genetics, SCV000664462.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

The p.L163F variant (also known as c.487C>T), located in coding exon 3 of the VHL gene, results from a C to T substitution at nucleotide position 487. The leucine at codon 163 is replaced by phenylalanine, an amino acid with highly similar properties. This alteration has been reported in multiple individuals with a personal and/or family history of VHL-associated disease (Tong AL et al. Ann. N. Y. Acad. Sci., 2006 Aug;1073:203-7; Pandit R et al. Eur. J. Endocrinol., 2016 12;175:X3; Lomte N et al. Fam Cancer, 2018 Jul;17:441-449; Goldstein M et al. AACE Clin Case Rep, 2020 May;6:e193-e196; Ambry internal data). Further, alterations at the same codon, p.L163P and p.L163R, have been reported in individuals with presumed sporadic Von Hippel-Lindau (VHL), as well as isolated pheochromocytoma (Cho HJ et al, J. Korean Med. Sci. 2009 Feb; 24(1):77-83; Sansó G et al, Am. J. Hypertens. 2004 Dec; 17(12 Pt 1):1107-11). Based on internal structural assessment, this alteration destabilizes the VHL elongin binding domain (Van Molle I et al. Chem. Biol., 2012 Oct;19:1300-12). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.

#	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: May 1, 2024

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