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]

Link to SEPIO compliant JSON-LD document

CA290954352

Gene: ITGA2B

Condition: Glanzmann's thrombasthenia

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 4944e895-ed84-4165-98c9-907bd669255d

HGVS expressions

NM_000419.5:c.917dup

NM_000419.3:c.917dup

NM_000419.4:c.917dup

ENST00000262407.5:c.917dup

ENST00000589645.5:n.368dup

ENST00000591990.5:n.462dup

ENST00000592075.5:n.286dup

ENST00000592226.5:n.157dup

ENST00000592253.5:n.425dup

NC_000017.11:g.44384113dup

CM000679.2:g.44384113dup

NC_000017.10:g.42461481dup

CM000679.1:g.42461481dup

NC_000017.9:g.39817007dup

NG_008331.1:g.10393dup

Pathogenic

PM3_Supporting PM2_Supporting PVS1

PP4

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_000419.4:c.917dup (p.Arg307GlufsTer22) 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 heterozygosity in an individual with a laboratory phenotype (platelet aggregation and surface expression) consistent with Glanzmann's thrombasthenia (GT) (CabGT-2, PMID: 20020534), however sufficient bleeding phenotype information to confirm if the individual's phenotype is specific for GT was not provided. 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, PM2_Supporting, PM3_Supporting.

PM3_Supporting

This variant has been reported in heterozygosity in an individual harboring a second heterozygous ITGA2B variant (c.1913dup, p.Cys639MetfsTer22) provisionally classified as pathogenic by the Platelet Disorders VCEP without confirmation of phase (CabGT-2, PMID: 20020534). This co-occurrence earns 0.5 points, sufficient to apply PM3_supporting.

PM2_Supporting

This variant is rare in population databases, having been observed in 1/64582 alleles in the non-Finnish European population in gnomAD v3 and not observed in gnomAD v2.1.1. The frequency of this variant is below the 1/10000 allele threshold required to apply PM2_supporting.

PVS1

This variant introduces a frameshift resulting in a premature termination codon in exon 11/30. The resulting mRNA product is predicted to undergo nonsense mediated decay, leading to loss of normal protein function.

PP4

This variant was reported in heterozygosity in one individual (originally reported as CabGT-2 in PMID: 20020534, additional information reported as 311 in Glanzmann's Thrombasthenia Database) with a platelet aggregation and surface expression laboratory phenotype consistent with Glanzmann's Thrombasthenia (abnormal response to two agonists and normal response to ristocetin; flow cytometry demonstrated reduced GPIIb and GPIIIa surface expression). However, sufficient bleeding phenotype information to meet PP4 was not provided.

Approved on: 2020-10-14

Published on: 2021-01-22

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