NM_000551.4(VHL):c.278_279delinsTT (p.Gly93Val) AND multiple conditions

This record was updated by the submitter. Please see the current version.

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Nov 14, 2020
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:: RCV000707314.5

Allele description

NM_000551.4(VHL):c.278_279delinsTT (p.Gly93Val)

Gene:

VHL:von Hippel-Lindau tumor suppressor [Gene - OMIM - HGNC]

Variant type:

Indel

Cytogenetic location:

3p25.3

Genomic location:

Preferred name:

NM_000551.4(VHL):c.278_279delinsTT (p.Gly93Val)

HGVS:

NC_000003.12:g.10142125_10142126delinsTT
NG_008212.3:g.5491_5492delinsTT
NM_000551.4:c.278_279delinsTTMANE SELECT
NM_001354723.2:c.278_279delinsTT
NM_198156.3:c.278_279delinsTT
NP_000542.1:p.Gly93Val
NP_001341652.1:p.Gly93Val
NP_937799.1:p.Gly93Val
LRG_322:g.5491_5492delinsTT
NC_000003.11:g.10183809_10183810delinsTT
NM_000551.3:c.278_279delGCinsTT

Protein change:

G93V

Links:

dbSNP: rs1559426072

NCBI 1000 Genomes Browser:

rs1559426072

Molecular consequence:

NM_000551.4:c.278_279delinsTT - missense variant - [Sequence Ontology: SO:0001583]
NM_001354723.2:c.278_279delinsTT - missense variant - [Sequence Ontology: SO:0001583]
NM_198156.3:c.278_279delinsTT - 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
SCV000836405	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Nov 14, 2020)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 11409863, 8707293, 22136840, 17922902, 10095351, 12000816, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000836405

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Nov 14, 2020)

germline

clinical testing

PubMed (7)
[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

DHPLC-based germline mutation screening in the analysis of the VHL tumor suppressor gene: usefulness and limitations.

Klein B, Weirich G, Brauch H.

Hum Genet. 2001 May;108(5):376-84.

PubMed [citation]

PMID:: 11409863

Mutations in the VHL tumor suppressor gene and associated lesions in families with von Hippel-Lindau disease from central Europe.

Glavac D, Neumann HP, Wittke C, Jaenig H, Masek O, Streicher T, Pausch F, Engelhardt D, Plate KH, Höfler H, Chen F, Zbar B, Brauch H.

Hum Genet. 1996 Sep;98(3):271-80.

PubMed [citation]

PMID:: 8707293

See all PubMed Citations (7)

Details of each submission

From Invitae, SCV000836405.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

A different missense substitution at this codon (p.Gly93Ser) has been determined to be pathogenic (PMID: 11409863, 12000816, 8707293, 22136840, 17922902). This suggests that the glycine residue is critical for VHL protein function and that other missense substitutions at this position may also be pathogenic. 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. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This missense change has been observed in individual(s) with clinical features of von Hippel-Lindau syndrome (PMID: 10095351, 12000816, Invitae, external communication). ClinVar contains an entry for this variant (Variation ID: 583075). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with valine at codon 93 of the VHL protein (p.Gly93Val). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and valine.

#	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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