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.629G>C

CA400023389

953047 (ClinVar)

Gene: ITGB3 (HGNC:3690)

Condition: Glanzmann thrombasthenia (MONDO:0010119)

Inheritance Mode: Autosomal recessive inheritance

UUID: 4a2ca60f-e835-4227-b8e2-93600aff608f

Approved on: 2023-11-02

Published on: 2023-11-03

HGVS expressions

NM_000212.2:c.629G>C

NC_000017.11:g.47286274G>C

CM000679.2:g.47286274G>C

NC_000017.10:g.45363640G>C

CM000679.1:g.45363640G>C

NC_000017.9:g.42718639G>C

NG_008332.2:g.37433G>C

ENST00000559488.7:c.629G>C

ENST00000559488.5:c.629G>C

ENST00000560629.1:c.594G>C

ENST00000571680.1:c.629G>C

NM_000212.3:c.629G>C

NM_000212.3(ITGB3):c.629G>C (p.Cys210Ser)

Pathogenic

PS3 PP3 PP1 PM3 PM2_Supporting PP4_Moderate

Evidence Links 1

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

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Platelet Disorders VCEP

The NM_000212.2:c.628T>A (p.Cys210Ser) missense variant has been reported in the compound heterozygous state (in trans with Pathogenic variant Pro189Ser) in one proband and his brother (PMID: 31565851) with a phenotype highly specific to GT (PM3, PP4_moderate). Multiple lines of computational evidence support a deleterious effect with a REVEL score of 0.963 (PP3). The variant is absent from population databases, including gnomADv2.1.1 (PM2_supporting). Functional studies show reduced binding to fibrinogen when expressed in CHO cells (PMID: 14690453; PS3). In summary this variant meets criteria to be classified as Pathogenic for autosomal recessive Glanzmann thrombasthenia. GT-specific criteria applied: PP4_moderate, PP3, PP1, PM2_supporting, PM3, PS3.

PS3

In PMID: 14690453 the authors transiently expressed the Cy210Ser (referred to as Cys184Ser) mutant together with WT GPIIb in CHO cells and tested their ability to bind to soluble fibrinogen by flow cytometry. The Cys210Ser mutant was expressed but did not bind to fibrinogen even when activated with mAb PT25-2.

Transiently expressed the Cy210Ser (referred to as Cys184Ser) mutant together with WT GPIIb in CHO cells and tested their ability to bind to soluble fibrinogen by flow cytometry. The Cys210Ser mutant was expressed but did not bind to fibrinogen even when activated with mAb PT25-2. PubMed:14690453

PP3

SIFT (Damaging), Polyphen2-HDIV 1 (probably Damaging), and Mutation Taster (disease causing) agree that this variant has a deleterious effect and the REVEL score is 0.936, above the >0.7 threshold.

PP1

The proband and brother of PMID: 31565851 share the compound heterozygous genotype of Pro189Ser and Cys210Ser. Both are diagnosed with both GT and macrothrombocytopenia.

PM3

The patient is compound heterozygous for Pro189Ser (classified as Pathogenic by the ClinGen Platelet Disorders VCEP) and Cys210Ser . The variants are in trans as confirmed by independent segregation in the next generation (PM3; PMID: 31565851).

PM2_Supporting

This variant is absent from all population cohorts in gnomAD, ExAC, 1000 Genomes, and ESP.

PP4_Moderate

The proband of PMID: 31565851 meets the criteria for PP4; including mucocutaneous bleeding, impaired aggregation with all agonists except ristocetin, and reduced surface expression of αIIbβ3.

Curation History

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