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.1456del

CA915940376

Gene: ITGB3 (HGNC:3690)

Condition: Glanzmann thrombasthenia (MONDO:0100326)

Inheritance Mode: Autosomal recessive inheritance

UUID: 156ca3cf-d423-482c-9bdc-648db7c5bf10

Approved on: 2021-08-17

Published on: 2021-08-20

HGVS expressions

NM_000212.3:c.1456del

NC_000017.11:g.47292334del

CM000679.2:g.47292334del

NC_000017.10:g.45369700del

CM000679.1:g.45369700del

NC_000017.9:g.42724699del

NG_008332.2:g.43493del

ENST00000559488.7:c.1456del

ENST00000559488.5:c.1456del

ENST00000560629.1:n.1421del

NM_000212.2:c.1456del

Pathogenic

PM3_Supporting PVS1 PP4_Moderate PM2_Supporting

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 p.Cys486Alafs*183 variant in exon 10 of ITGB3 gene is predicted to introduce a premature stop codon 183 amino acids downstream and result in NMD. This variant is absent from large population databases including gnomAD. It has been reported previously in compound heterozygous state with another pathogenic variant (p.Arg287Serfs*34) in one proband who meets the ClinGen PD-VCEP criteria for the GT phenotype. The variant meets criteria for PVS1, PP4_moderate, PM3_supporting and PM2_supporting and is classified as pathogenic.

PM3_Supporting

The p.Cys486Alafs variant was reported to occur in compound heterozygous state in one proband with another frameshift variant, p.Arg287Serfs, which has been classified as pathogenic by ClinGen PD-VCEP. 0.5 points.

PVS1

The p.Cys486Alafs variant located in exon 10 is predicted to introduce a premature stop codon 183 amino acids downstream, resulting in NMD.

PP4_Moderate

One individual with the p.Cys486Alafs variant in compound heterozygous state presented with significant mucocutaneous bleeding. Platelet aggregometry demonstrated absence of platelet aggregation with 3 platelet agonists and normal aggregation with ristocetin. Flowcytometry for surface expression of glycoproteins was not performed. Sanger sequencing ensured coverage of exons and splice sites of the ITGA2B and ITGB3 genes as well as untranslated regions (UTR). PMID:25728920 PP4_moderate applied.

PM2_Supporting

The p.Cys486Alafs variant is absent from large population databases including gnomAD.

Curation History

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