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_000419.4(ITGA2B):c.2614C>A (p.Leu872Met)

CA8602631

323544 (ClinVar)

Gene: ITGA2B

Condition: Glanzmann's thrombasthenia

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 13c5f175-a7d2-4a5c-8cea-f796b56c87d4

Approved on: 2020-06-04

Published on: 2021-01-22

HGVS expressions

NM_000419.4:c.2614C>A

NM_000419.4(ITGA2B):c.2614C>A (p.Leu872Met)

NM_000419.3:c.2614C>A

NM_000419.5:c.2614C>A

ENST00000262407.5:c.2614C>A

ENST00000587295.5:n.253+129C>A

ENST00000592462.5:n.1409C>A

NC_000017.11:g.44375704G>T

CM000679.2:g.44375704G>T

NC_000017.10:g.42453072G>T

CM000679.1:g.42453072G>T

NC_000017.9:g.39808598G>T

NG_008331.1:g.18802C>A

Benign

BA1 BS3 BP4

Evidence Links 1

Expert Panel

Platelet Disorders VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Platelet Disorders VCEP

The NM_000419.4:c.2614C>A variant that results in the Leu872Met amino acid change is reported at frequencies (2%; 0.02101 in the African subpopulation, with 5 homozygotes, in gnomAD) higher than the recommended threshold of 0.24%, in population databases. The variant is not reported in any GT patients in the literature. Experimental evidence suggests no impact to expression or function of the αIIbβ3 complex. Computation evidence also suggests no impact with a REVEL score of 0.136. In summary, based on the available evidence, the Leu872Met variant is classified as "benign". GT-specific criteria applied: BA1, BS3, and BP4.

BA1

The variant, Leu872Met is reported at high frequencies across many population databases. In gnomAD, this variant is reported at a frequency of 0.02101 (threshold >0.0024) in the African subpopulation with 5 homozygotes. The evidence meets criteria for BA1.

BS3

Experimental evidence reveals no impact of Leu872Pro variant on αIIbβ3 complex expression or function.

Wildtype (Leu-872) and variant (Met-872) cDNA constructs were expressed in HEK293 cells. Flow cytometry analysis showed similar expression levels of αIIbβ3 complex between wild-type and mutant-expressing cells. Fibrinogen binding was also unaffected in mutant cells. PubMed:22738334

BP4

REVEL score of 0.136 is below the threshold of <0.25

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