NM_000551.4(VHL):c.416C>T (p.Ser139Phe) AND multiple conditions

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Jan 15, 2024
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:: RCV001317982.7

Allele description [Variation Report for NM_000551.4(VHL):c.416C>T (p.Ser139Phe)]

NM_000551.4(VHL):c.416C>T (p.Ser139Phe)

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.416C>T (p.Ser139Phe)

HGVS:

NC_000003.12:g.10146589C>T
NG_008212.3:g.9955C>T
NG_046756.1:g.4351C>T
NM_000551.4:c.416C>TMANE SELECT
NM_001354723.2:c.*18-3198C>T
NM_198156.3:c.341-3198C>T
NP_000542.1:p.Ser139Phe
NP_000542.1:p.Ser139Phe
LRG_322t1:c.416C>T
LRG_322:g.9955C>T
LRG_322p1:p.Ser139Phe
NC_000003.11:g.10188273C>T
NM_000551.3:c.416C>T

Protein change:

S139F

Links:

dbSNP: rs587780732

NCBI 1000 Genomes Browser:

rs587780732

Molecular consequence:

NM_001354723.2:c.*18-3198C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_198156.3:c.341-3198C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_000551.4:c.416C>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
SCV001508666	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Jan 15, 2024)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 25078357, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001508666

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Jan 15, 2024)

germline

clinical testing

PubMed (2)
[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

Germline mutation of Glu70Lys is highly frequent in Korean patients with von Hippel-Lindau (VHL) disease.

Hwang S, Ku CR, Lee JI, Hur KY, Lee MS, Lee CH, Koo KY, Lee JS, Rhee Y.

J Hum Genet. 2014 Sep;59(9):488-93. doi: 10.1038/jhg.2014.61. Epub 2014 Jul 31.

PubMed [citation]

PMID:: 25078357

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001508666.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 139 of the VHL protein (p.Ser139Phe). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with von Hippel-Lindau syndrome (PMID: 25078357). ClinVar contains an entry for this variant (Variation ID: 216478). 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 currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely 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: Nov 10, 2024

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