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_000419.5:c.527C>A

CA8603447

953014 (ClinVar)

Gene: ITGA2B (HGNC:3674)

Condition: Glanzmann's thrombasthenia (MONDO:0010119)

Inheritance Mode: Autosomal recessive inheritance

UUID: 69629f95-09fa-4449-82e5-95598024737d

Approved on: 2021-03-05

Published on: 2021-03-05

HGVS expressions

NM_000419.5:c.527C>A

NC_000017.11:g.44385598G>T

CM000679.2:g.44385598G>T

NC_000017.10:g.42462966G>T

CM000679.1:g.42462966G>T

NC_000017.9:g.39818492G>T

NG_008331.1:g.8908C>A

ENST00000262407.5:c.527C>A

NM_000419.3:c.527C>A

NM_000419.4:c.527C>A

Likely Pathogenic

PS3_Moderate PM2_Supporting PM5 PP3

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.527C>A (p.Pro176His) missense variant was identified from an individual in The National Heart, Lung and Blood Institute Exome Sequencing Project (ESP) whose full genotype and phenotype were not reported. It occurs at an extremely low frequency of 0.000008248 in the African population of gnomAD. It is predicted to have a deleterious effect (REVEL score of 0.913) which was confirmed by functional studies showing virtually no mature GPIIb protein in transfected HEK293 cells (PMID: 25827233). This variant occurs at the same residue as the pathogenic variant Pro176Ala. In summary, this variant meets criteria to be classified as Likely Pathogenic for GT. GT specific criteria used: PS3_moderate, PM2_Supporting, PM5, PP3.

PS3_Moderate

In PMID: 25827233 the Pro176His GPIIb was expressed in HEK293 cells which showed virtually no mature GPIIb protein by immunoblot.

The Pro176His GPIIb was expressed in HEK293 cells which showed virtually no mature GPIIb protein by immunoblot or surface expression of the GPIIb/IIIa complex by flow cytometry (<5% positive cells). PubMed:25827233

PM2_Supporting

This variant is at an extremely low frequency (below the <1/10,000 threshold) with an overall allele frequency from gnomAD of 0.000008248 and MAF of 0.00006689 (1/14,950 alleles) in the African population.

PM5

The Pro176His variant occurs at the same residue as the previously classified Pathogenic Pro176Ala variant. The additional likely pathogenic Pro176Leu variant is not considered here.

PP3

SIFT (Damaging), Polyphen2-HDIV (probably Damaging), and Mutation Taster (disease causing) agree that this variant has a deleterious effect and the REVEL score is 0.913, above the >0.7 threshold.

Curation History

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