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]

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CA290948990

Gene: ITGA2B

Condition: Glanzmann's thrombasthenia

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: f60ee421-a048-4775-94a7-1ee36dbd9011

HGVS expressions

NM_000419.5:c.1913dup

NC_000017.11:g.44378676dup

CM000679.2:g.44378676dup

NC_000017.10:g.42456044dup

CM000679.1:g.42456044dup

NC_000017.9:g.39811570dup

NG_008331.1:g.15830dup

NM_000419.3:c.1913dup

NM_000419.4:c.1913dup

ENST00000262407.5:c.1913dup

ENST00000592462.5:n.708dup

Pathogenic

PM3_Supporting PM2_Supporting PVS1 PP4_Strong

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 ITGA2B frameshift variant NM_000419.5:c.1913dup (p.Cys639MetfsTer22) introduces a premature termination codon and the resulting mRNA product is predicted to undergo nonsense mediated decay, leading to loss of normal protein function. This variant has been observed in homozygosity in one individual (Patient LF, PMID: 12083483) and heterozygosity in two individuals (CabGT-2, PMID: 20020534 and Patient ER, PMID: 12083483), at least one of which was reported to have a phenotype specific for Glanzmann's thrombasthenia (GT). Furthermore, this variant is extremely rare in population databases. In summary, this variant meets criteria to be classified as pathogenic for GT. GT-specific criteria applied: PVS1, PP4_strong, PM2_supporting, PM3_supporting.

PM3_Supporting

This variant has been reported in homozygosity in one individual (Patient LF, PMID: 12083483), earning 0.5 points and sufficient to meet PM3_supporting. This variant has also been observed in heterozygosity in two individuals (CabGT-2, PMID: 20020534 and Patient ER, PMID: 12083483). The second ITGA2B variant identified in CabGT-2 (c.917dup, p.Arg307GlufsTer22) is provisionally classified by the Platelet Disorders VCEP as pathogenic and the phase of the two variants is unknown. However, this evidence contributed to PM3 in the classification of p.Arg307GlufsTer222 and was not counted for p.Cys639MetfsTer22 to avoid circularity. A second variant was not identified in Patient ER, so this occurrence earns 0 points.

PM2_Supporting

This variant is rare in control population databases. It was observed in heterozygosity in a single individual in gnomAD v2.1.1 (MAF in non-Finnish European population: 0.00006484 (1/15422 alleles); overall allele frequency: 0.00003186 (1/31392 alleles)) and, similarly, in heterozygosity in a single individual in gnomad v3 (MAF in non-Finnish European population: 0.00001548 (1/64584 alleles); overall allele frequency: 0.000006977 (1/143318 alleles)). This frequency is below the VCEP-established threshold of fewer than 1 in 10,000 alleles, meeting the criterion to apply PM2_supporting.

PVS1

This variant introduces a frameshift in exon 19/30 resulting in a premature termination codon in the following exon (exon 20/30). The resulting mRNA product is predicted to undergo nonsense mediated decay, leading to loss of normal protein function.

PP4_Strong

This variant was reported in homozygosity in one individual (Patient LF, PMID: 12083483) and heterozygosity in two individuals (CabGT-2, PMID: 20020534 and Patient ER, PMID: 12083483). At least one of these individuals (Patient LF, PMID: 12083483) meets all requirements for PP4 at an upgraded strength of strong (PP4_strong): gastrointestinal bleeding; absent platelet aggregation in response to physiologic agonists except normal response to ristocetin; flow cytometry showed <10% expression of GPIIb and GPIIIa; direct sequencing of all exons and intron/exon boundaries of ITGA2B and ITGB3.

Approved on: 2020-12-07

Published on: 2021-01-22

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