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_000419.5:c.961G>T

CA399804768

996170 (ClinVar)

Gene: ITGA2B (HGNC:3674)

Condition: Glanzmann thrombasthenia (MONDO:0010119)

Inheritance Mode: Autosomal recessive inheritance

UUID: 5738e7ef-8f53-4bd1-960e-21c223060287

Approved on: 2024-02-20

Published on: 2024-02-20

HGVS expressions

NM_000419.5:c.961G>T

NC_000017.11:g.44383931C>A

CM000679.2:g.44383931C>A

NC_000017.10:g.42461299C>A

CM000679.1:g.42461299C>A

NC_000017.9:g.39816825C>A

NG_008331.1:g.10575G>T

ENST00000262407.6:c.961G>T

ENST00000648408.1:c.392G>T

ENST00000262407.5:c.961G>T

ENST00000589645.5:n.412G>T

ENST00000591990.5:n.506G>T

ENST00000592226.5:n.201G>T

NM_000419.3:c.961G>T

NM_000419.4:c.961G>T

NM_000419.5(ITGA2B):c.961G>T (p.Gly321Trp)

Likely Pathogenic

PP4_Strong PM2_Supporting PP3

PM5 PM3

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

PDF

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Platelet Disorders VCEP

The NM_000419.5(ITGA2B):c.962G>T (p.Gly321Trp) missense variant has been reported in at least one compound heterozygous GT57 proband (PMID:25728920). GT57 of PMID:25728920 meets the criteria for PP4_Strong; including mucocutaneous bleeding, impaired aggregation with all agonists except ristocetin, and reduced surface expression of αIIbβ3 measured by flow cytometry. The variant is absent from all population database cohorts, including gnomADv4.0 (PM2_supporting) and is predicted deleterious (REVEL score 0.95; PP3). In summary this variant meets criteria to be classified as likely pathogenic for GT. GT-specific criteria applied: PM2_Supporting, PP3, and PP4_Strong.

PP4_Strong

GT57 of PMID:25728920 meets the criteria for PP4_Strong; including mucocutaneous bleeding, impaired aggregation with all agonists except ristocetin, and reduced surface expression of αIIbβ3 measured by flow cytometry. ITGA2B and ITGB3 were sequenced across all exons and intron/exon boundaries.

PM2_Supporting

This variant is absent from all population cohorts in gnomADv4.0 (PM2_supporting).

PP3

REVEL score of 0.95 is above the >.0.7 threshold to support a deleterious effect.

PM5

The Gly321Trp variant occurs at the same residue as Gly321Val (classified likely pathogenic by the PD-EP). Not considered here to avoid circularity.

PM3

GT57 of PMID: 25728920 is compound heterozygous for Gly321Trp and Phe191Val (classified Likely Pathogenic by the PD-EP). Confirmation of the trans relationship was not reported. 0.25pt

Curation History

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