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_000212.3:c.1980C>A

CA400032983

Gene: ITGB3 (HGNC:3690)

Condition: Glanzmann thrombasthenia (MONDO:0100326)

Inheritance Mode: Autosomal recessive inheritance

UUID: 184c3689-ab69-40b9-8f76-205700d2d0ae

Approved on: 2021-06-30

Published on: 2021-12-23

HGVS expressions

NM_000212.3:c.1980C>A

NC_000017.11:g.47300544C>A

CM000679.2:g.47300544C>A

NC_000017.10:g.45377910C>A

CM000679.1:g.45377910C>A

NC_000017.9:g.42732909C>A

NG_008332.2:g.51703C>A

ENST00000559488.7:c.1980C>A

ENST00000559488.5:c.1980C>A

ENST00000560629.1:n.1945C>A

NM_000212.2:c.1980C>A

Pathogenic

PVS1 PP4_Strong PM2_Supporting

PM3

Evidence Links 0

Expert Panel

Platelet Disorders VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Platelet Disorders VCEP

The NM_000212.3(ITGB3):c.1980C>A (p.Tyr660Ter) nonsense variant creates a premature stop codon in exon 12/15 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). At least one proband has been reported with this variant, GT23 of PMID: 29675921 meets the criteria for PP4_strong. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1, PM2_supporting, PP4_strong. (VCEP specifications version 2; date of approval xx/xx/xxxx)

PVS1

The NM_000212.3(ITGB3):c.1980C>A (p.Tyr660Ter) is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 12/15 and is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1).

PP4_Strong

GT23 of PMID: 29675921 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 gnomAD v2.1.1 (PM2_Supporting).

PM3

GT23 is compound heterozygous for Tyr660Ter and Gly716Val (not yet classified by the PD-VCEP). Confirmation of trans phase was not reported. Not counted here to avoid circularity. 0pt

Curation History

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