NM_000551.4(VHL):c.319C>A (p.Arg107Ser) AND multiple conditions

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jan 2, 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:: RCV003805279.2

Allele description [Variation Report for NM_000551.4(VHL):c.319C>A (p.Arg107Ser)]

NM_000551.4(VHL):c.319C>A (p.Arg107Ser)

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.319C>A (p.Arg107Ser)

HGVS:

NC_000003.12:g.10142166C>A
NG_008212.3:g.5532C>A
NM_000551.4:c.319C>AMANE SELECT
NM_001354723.2:c.319C>A
NM_198156.3:c.319C>A
NP_000542.1:p.Arg107Ser
NP_000542.1:p.Arg107Ser
NP_001341652.1:p.Arg107Ser
NP_937799.1:p.Arg107Ser
LRG_322t1:c.319C>A
LRG_322:g.5532C>A
LRG_322p1:p.Arg107Ser
NC_000003.11:g.10183850C>A
NM_000551.3:c.319C>A
NR_176335.1:n.389C>A

Protein change:

R107S

Molecular consequence:

NM_000551.4:c.319C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354723.2:c.319C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_198156.3:c.319C>A - missense variant - [Sequence Ontology: SO:0001583]
NR_176335.1:n.389C>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]

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
SCV004592975	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 2, 2024)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 26230854, 12202531, 19336503, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004592975

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 2, 2024)

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

Bioinformatic Challenges in Clinical Diagnostic Application of Targeted Next Generation Sequencing: Experience from Pheochromocytoma.

Crona J, Ljungström V, Welin S, Walz MK, Hellman P, Björklund P.

PLoS One. 2015;10(7):e0133210. doi: 10.1371/journal.pone.0133210.

PubMed [citation]

PMID:: 26230854
PMCID:: PMC4521794

Retinal hemangioblastoma in von Hippel-Lindau disease: a clinical and molecular study.

Dollfus H, Massin P, Taupin P, Nemeth C, Amara S, Giraud S, Béroud C, Dureau P, Gaudric A, Landais P, Richard S.

Invest Ophthalmol Vis Sci. 2002 Sep;43(9):3067-74.

PubMed [citation]

PMID:: 12202531

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004592975.1

#	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 arginine, which is basic and polar, with serine, which is neutral and polar, at codon 107 of the VHL protein (p.Arg107Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of von Hippel-Lindau (VHL) syndrome (PMID: 26230854; Invitae). 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%. This variant disrupts the p.Arg107 amino acid residue in VHL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12202531, 19336503). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as 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: Sep 29, 2024

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