Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Variant: NM_000212.2(ITGB3):c.761A>G (p.Gln254Arg)

Curation Version - 2.0
Curation History
JSON LD for Version 2.0

CA400023678

627131 (ClinVar)

Gene: ITGB3

Condition: Glanzmann thrombasthenia

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 7ebcee0b-01ec-4a5f-aefc-a7c698f2c6f6

Approved on: 2023-12-19

Published on: 2023-12-19

HGVS expressions

NM_000212.2:c.761A>G

NM_000212.2(ITGB3):c.761A>G (p.Gln254Arg)

NC_000017.11:g.47286406A>G

CM000679.2:g.47286406A>G

NC_000017.10:g.45363772A>G

CM000679.1:g.45363772A>G

NC_000017.9:g.42718771A>G

NG_008332.2:g.37565A>G

ENST00000559488.7:c.761A>G

ENST00000559488.5:c.761A>G

ENST00000560629.1:c.726A>G

ENST00000571680.1:c.761A>G

NM_000212.3:c.761A>G

NM_000212.3(ITGB3):c.761A>G (p.Gln254Arg)

Likely Pathogenic

PP4_Strong PP3 PM5_Supporting PM3_Supporting PM2_Supporting

Evidence Links 0

Expert Panel

Platelet Disorders VCEP

Criteria Specification Information

Criteria Specification: ClinGen Platelet Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 2.1

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Platelet Disorders VCEP

NM_000212.2(ITGB3):c.761A>G (p.Gln254Arg) missense variant has been reported in at least one homozygous GT proband (PMID: 31064749; PM3_Supporting). Personal communication with the authors provided sufficient information to apply PP4_strong; including impaired aggregation with at least 3 agonists, an expected ristocetin response, and flow cytometry revealed <5% expression of GpIIb/IIIa. The variant is absent from all population databases including gnomAD (PM2_Supporting). Computational evidence supports a deleterious effect with a REVEL score of 0.951 (PP3). It occurs at the same amino acid residue as Likely Pathogenic variant Gln254Lys (PM5_Supporting). In summary this variant meets criteria to be classified as likely pathogenic for GT. GT-specific criteria applied: PM2_Supporting,PM3_Supporting, PP3, PP4_strong, and PM5_Supporting.

PP4_Strong

The variant has been reported in one patient in PMID: 31064749, however phenotypic details are not provided. Personal communication with the authors provided sufficient information to apply PP4_strong; including impaired aggregation with at least 3 agonists, an expected ristocetin response, and flow cytometry revealed <5% expression of GpIIb/IIIa. These data were internal laboratory data supplied to the authors. Additionally, there was full sequencing of ITGA2B and ITGB3 with all consensus coding sequences, the first and last 100 bp of introns, 5’ and 3’ UTRs, regions 1,000bp upstream of the transcription start site and the position of known pathogenic variants.

PP3

REVEL score of 0.951 is above the >.0.7 threshold, in support of a deleterious effect.

PM5_Supporting

The additional variant Gln254Lys has also been identified at this amino acid residue. Gln254Lys has been classified as Likely Pathogenic by the PD-VCEP.

PM3_Supporting

This variant has been reported homozygous in one patient in PMID: 31064749.

PM2_Supporting

This variant is absent from all population cohorts in gnomAD, ExAC, 1000 Genomes, and ESP.

Curation History

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