NM_000551.4(VHL):c.203C>T (p.Ser68Leu) AND multiple conditions

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Jul 18, 2022
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:: RCV001046095.7

Allele description [Variation Report for NM_000551.4(VHL):c.203C>T (p.Ser68Leu)]

NM_000551.4(VHL):c.203C>T (p.Ser68Leu)

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.203C>T (p.Ser68Leu)

HGVS:

NC_000003.12:g.10142050C>T
NG_008212.3:g.5416C>T
NM_000551.4:c.203C>TMANE SELECT
NM_001354723.2:c.203C>T
NM_198156.3:c.203C>T
NP_000542.1:p.Ser68Leu
NP_000542.1:p.Ser68Leu
NP_001341652.1:p.Ser68Leu
NP_937799.1:p.Ser68Leu
LRG_322t1:c.203C>T
LRG_322:g.5416C>T
LRG_322p1:p.Ser68Leu
NC_000003.11:g.10183734C>T
NM_000551.3:c.203C>T

Protein change:

S68L

Links:

dbSNP: rs869025617

NCBI 1000 Genomes Browser:

rs869025617

Molecular consequence:

NM_000551.4:c.203C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354723.2:c.203C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_198156.3:c.203C>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
SCV001209983	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Jul 18, 2022)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 10627136, 12000816, 17661816, 27785399, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001209983

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Jul 18, 2022)

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

Variable penetrance of familial pheochromocytoma associated with the von Hipple Lindau gene mutation, S68W. Mutations in brief no. 150. Online.

Martin R, Hockey A, Walpole I, Goldblatt J.

Hum Mutat. 1998;12(1):71.

PubMed [citation]

PMID:: 10627136

Germ-line mutations in nonsyndromic pheochromocytoma.

Neumann HP, Bausch B, McWhinney SR, Bender BU, Gimm O, Franke G, Schipper J, Klisch J, Altehoefer C, Zerres K, Januszewicz A, Eng C, Smith WM, Munk R, Manz T, Glaesker S, Apel TW, Treier M, Reineke M, Walz MK, Hoang-Vu C, Brauckhoff M, et al.

N Engl J Med. 2002 May 9;346(19):1459-66.

PubMed [citation]

PMID:: 12000816

See all PubMed Citations (5)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001209983.5

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

Description

ClinVar contains an entry for this variant (Variation ID: 625222). 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. This variant disrupts the p.Ser68 amino acid residue in VHL. Other variant(s) that disrupt this residue have been observed in individuals with VHL-related conditions (PMID: 10627136, 12000816, 17661816, 27785399), which suggests that this may be a clinically significant amino acid residue. 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. This missense change has been observed in individual(s) with clinical features of VHL (Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 68 of the VHL protein (p.Ser68Leu).

#	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

ClinVar

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