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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Variant: NM_000419.5(ITGA2B):c.2621T>G (p.Ile874Ser)

CA115831

2891 (ClinVar)

Gene: ITGA2B

Condition: Glanzmann's thrombasthenia

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 9b68cd08-b338-44bf-bae0-7e8866b9a1b2

HGVS expressions

NM_000419.5:c.2621T>G

NM_000419.5(ITGA2B):c.2621T>G (p.Ile874Ser)

NC_000017.11:g.44375697A>C

CM000679.2:g.44375697A>C

NC_000017.10:g.42453065A>C

CM000679.1:g.42453065A>C

NC_000017.9:g.39808591A>C

NG_008331.1:g.18809T>G

NM_000419.3:c.2621T>G

NM_000419.4:c.2621T>G

ENST00000262407.5:c.2621T>G

ENST00000587295.5:n.253+136T>G

ENST00000592462.5:n.1416T>G

Benign

BA1 BP4 BP2

BS2

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 c.2621T>G (p.Ile874Ser) missense variant has been reported many times in the literature as an alloantigenic site. This variant has been observed in cis with several other Glanzmann thrombasthenia variants, including the pathogenic Tyr471Ter and c.1440-13_1440-1del ITGA2B variants and the Pro189Ser ITGB3 variant (PMID: 25728920). It is present in gnomAD at an overall allele frequency of 0.39177 (and 0.43954 in the non-Finnish European population). Computational evidence suggest no impact on the gene/gene product, with a REVEL score of 0.055. In summary, this variant meets criteria to be classified as benign for GT. GT-specific criteria applied: BA1, BP2, BP4.

BA1

The overall allele frequency in gnomAD is 0.39177 with a MAF of 0.43954 (9494/21,600 alleles) in the Finnish European population. This is above the threshold of >0.0024.

BP4

Computational evidence suggests no impact on the gene or gene product with a REVEL score of 0.055, below the <0.25 threshold.

BP2

This variant has been observed in cis with 20 other ITGA2B or ITGB3 variants in 16 GT patients from PMID: 27469266 and PMID: 25728920, including the Tyr471Ter and c.1440-13_1440-1del ITGA2B variants and the Pro189Ser ITGB3 variant, all of which have been classified as pathogenic by the Platelet Disorders VCEP.

BS2

Although homozygosity (18143 individuals in gnomAD cohort) has been reported in population databases of reportedly healthy individuals, phenotypic data is not available.

Approved on: 2020-11-10

Published on: 2021-01-22

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