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_000212.2:c.187C>T

Curation Version - 1.0
Curation History
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CA8622892

631774 (ClinVar)

Gene: ITGB3

Condition: Glanzmann's thrombasthenia

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 09d0fd53-4154-4560-a8c2-c5736646ca33

Approved on: 2020-09-04

Published on: 2021-01-28

HGVS expressions

NM_000212.2:c.187C>T

NC_000017.11:g.47283375C>T

CM000679.2:g.47283375C>T

NC_000017.10:g.45360741C>T

CM000679.1:g.45360741C>T

NC_000017.9:g.42715740C>T

NG_008332.2:g.34534C>T

ENST00000696963.1:c.187C>T

ENST00000559488.7:c.187C>T

ENST00000559488.5:c.187C>T

ENST00000560629.1:c.152C>T

ENST00000571680.1:c.187C>T

NM_000212.3:c.187C>T

Likely Pathogenic

PP4_Strong PS3_Moderate PM3_Supporting PP3 PM2_Supporting

PP1

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 missense variant, c.187C>T (p.Arg63Cys), has been reported in one compound heterozygous proband (PMID: 25728920). It occurs at an extremely low frequency, with an overall allele frequency in gnomAD of 0.00002476 (MAF of 0.00005012 in the East Asian population). SIFT, PolyPhen, and MutationTaster agree that the Arg63Cys variant is damaging/disease causing (REVEL score of 0.98). In transiently transfected COS‐7 cells expressing Arg63Cys mutant integrin FACS analysis showed 85% reduction of αIIbβ3Cys63 expression. In summary, this variant meets criteria to be classified as Likely Pathogenic for GT. GT-specific criteria applied: PS3_Moderate, PM2_Supporting, PM3_Supporting, PP3, and PP4_Strong.

PP4_Strong

One patient has been described in PMID: 25728920 with the Arg63Cys variant who meets the criteria for PP4_Strong; including mucocutaneous bleeding, impaired aggregation with all agonists except ristocetin, and reduced surface expression of αIIbβ3 measured by flow cytometry. ITGA2B and ITGB3 were sequenced across all exons and intron/exon boundaries.

Patient GT7, compound heterozygous for Arg63Cys, had a history of mucocutaneous bleeding (easy bruising and epistaxis) and a WHO bleeding score of 1. There was absent platelet aggregation with ADP and severely reduced with at least two additional agonists but normal ristocetin-induced aggregation. There was residual (10-15%) platelet expression of alphaIIb-beta3 confirmed by flow cytometry. No mention was made of platelet count. PubMed:25728920

PS3_Moderate

In transiently transfected COS‐7 cells expressing Arg63Cys mutant integrin FACS analysis showed 85% reduction of αIIbβ3Cys63 expression on transfected cells compared with wild type. Disruption of protein function was not assessed in PMID: 2572892.

PM3_Supporting

Arg63Cys has been reported in trans with the pathogenic variant Arg169Ter, however the phase has not been confirmed so it meets PM3_supporting.

In patient GT7 the Arg169Ter variant was reported in trans with c.187C>T p.Arg63Cys but the phase was not confirmed. 0.5pt PubMed:25728920

PP3

There is consensus among SIFT, PolyPhen, and MutationTaster that the Arg63Cys variant is damaging/disease causing. The REVEL score of 0.98 is above the 0.7 threshold.

PM2_Supporting

This variant occurs at an extremely low frequency, <1/10,000 alleles, with an overall allele frequency in gnomAD of 0.00002476 (MAF of 0.00005012 in the East Asian population, 1/19,954 alleles).

PP1

Patient GT7 of PMID: 25728920 has an affected brother however his genotype was not provided.

Patient GT7 has an affected brother however his genotype was not provided. PubMed:25728920

Curation History

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