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_000212.3:c.683G>A

CA8623025

1210168 (ClinVar)

Gene: ITGB3

Condition: Glanzmann thrombasthenia

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 8e03c08f-5f4d-4573-a400-b438e3874ad7

Approved on: 2024-09-05

Published on: 2024-09-30

HGVS expressions

NM_000212.3:c.683G>A

NC_000017.11:g.47286328G>A

CM000679.2:g.47286328G>A

NC_000017.10:g.45363694G>A

CM000679.1:g.45363694G>A

NC_000017.9:g.42718693G>A

NG_008332.2:g.37487G>A

ENST00000696963.1:c.683G>A

ENST00000559488.7:c.683G>A

ENST00000559488.5:c.683G>A

ENST00000560629.1:c.648G>A

ENST00000571680.1:c.683G>A

NM_000212.2:c.683G>A

Uncertain Significance

PP3 PM2_Supporting

PP4 PP1 PM3 BP2

Evidence Links 0

Expert Panel

Platelet Disorders VCEP

Criteria Specification Information

Criteria Specification: ClinGen Platelet Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 2.1

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Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Platelet Disorders VCEP

The p.Arg228His variant on ITGB3 gene is a missense variant that has been reported previously in the context of Glanzmann Thrombasthenia (PMID: 25728920). Multiple in silico tools predict this variant to be deleterious (REVEL score = 0.89; PP3). This variant is rare in large population databases with a MAF of 0.00008008 (6/74924) in the African subpopulation of gnomADv4.1 which is lower than the PD-VCEP threshold of <0.0001 (PM2_supporting). This variant has been reported in homozygosity in two symptomatic siblings who meet diagnostic criteria for GT phenotype (PMID: 25728920). However, the siblings are homozygous for both c.614+1G>T and Arg228His and while this splice variant is Likely Pathogenic an impact of the missense variant can not be excluded so this case has not been considered in the classification of this variant. This variant meets criteria for PP3 and PM2_supporting and is classified as a VUS.

PP3

REVEL score for this variant is 0.89 which is above the PD-VECP threshold of >0.70

PM2_Supporting

This variant is rare in large population databases with a MAF of 0.00008008 (6/74924) in the African subpopulation of gnomADv4.1 which is lower than the PD-VCEP threshold of <0.0001 (PM2_supporting).

PP4

Two related individuals (GT43a&b) had history of significant mucocutaneous bleeding, platelet aggregation was absent with three physiological agonists (but normal aggregation with ristocetin) and reduced (<5%) surface expression of αIIbβ3 demonstrated by flow cytometry. Sanger sequencing ensured coverage of exons and splice sites of the ITGA2B and ITGB3 genes as well as untranslated regions (UTR). (PMID: 25728920) Patients GT43a&b are homozygous for both c.614+1G>T and Arg228His, because the effect of each variant can not be determined independently no criteria have been applied based on patient information.

PP1

The p.Arg228His variant was found to co-segregate with disease in two related individuals (GT43a,b) with GT (PMID:25728920). Patients GT43a&b are homozygous for both c.614+1G>T and Arg228His, because the effect of each variant can not be determined independently no criteria have been applied based on patient information.

PM3

The p.Arg228His variant was found in the homozygous state in two related individuals (GT43a,b)with GT (PMID:25728920). However, since patients GT43a&b are homozygous for both c.614+1G>T and Arg228His, because the effect of each variant can not be determined independently no criteria have been applied based on patient information.

BP2

The p.Arg228His variant was found in the homozygous state in two related individuals (GT43a,b) with GT (PMID:25728920). However, this variant is co-expressed with a c.614+1G>T homozygous variant in the same individuals, which is predicted to affect the splice site of exon 4 (classified as Likely Pathogenic by the PD-VECP).

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