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_000212.3:c.941A>C

CA400025615

996159 (ClinVar)

Gene: ITGB3 (HGNC:3690)

Condition: Glanzmann thrombasthenia (MONDO:0010119)

Inheritance Mode: Autosomal recessive inheritance

UUID: 96a290ca-2034-477d-82dd-a8e62c4c5ce8

Approved on: 2023-12-19

Published on: 2023-12-19

HGVS expressions

NM_000212.3:c.941A>C

NC_000017.11:g.47289682A>C

CM000679.2:g.47289682A>C

NC_000017.10:g.45367048A>C

CM000679.1:g.45367048A>C

NC_000017.9:g.42722047A>C

NG_008332.2:g.40841A>C

ENST00000559488.7:c.941A>C

ENST00000559488.5:c.941A>C

ENST00000560629.1:c.906A>C

ENST00000571680.1:c.941A>C

NM_000212.2:c.941A>C

NM_000212.3(ITGB3):c.941A>C (p.Asp314Ala)

Likely Pathogenic

PP4_Moderate PP3 PM3_Supporting PM5_Supporting PM2_Supporting

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

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Platelet Disorders VCEP

The NM_000212.3(ITGB3):c.941A>C (p.Asp314Ala) missense variant has been reported at least once in literature, in a homozygous patient (PMID:20514620; PM3_supporting). The patient was demonstrated to have lack of platelet aggregation with three physiological agonists (normal with ristocetin) and this was confirmed by flow cytometry. Personal communication with the authors revealed the patient was treated for multiple mucocutaneous bleeding phenotypes (PP4_moderate). The variant is absent from all population database cohorts, including gnomAD (PM2_supporting) and is predicted deleterious (REVEL score 0.974; PP3). The Asp314Alal variant occurs at the same residue as Asp314Tyr (classified Likely Pathogenic by the PD-EP; PM5_supporting). In summary this variant meets criteria to be classified as likely pathogenic for GT. GT-specific criteria applied: PM2_supporting, PM3_supporitng, PM5_supporting, PP3, and PP4_moderate.

PP4_Moderate

PMID:20514620 reported a 7.5 year old male child who was demonstrated to have lack of platelet aggregation with three physiological agonists (normal with ristocetin) and this was confirmed by flow cytometry. Personal communication with the authors revealed the patient was treated for multiple mucocutaneous bleeding phenotypes. Unknown if there was full sequencing of the ITGB3 and ITGA2B genes.

PP3

REVEL score of 0.974 is above the impact threshold of 0.70 , Therefore PP3 is met.

PM3_Supporting

This variant has been reported in homozygous state in one proband. (PMID: 20514620) ) 0.5 points

PM5_Supporting

Another missense change (Asp314Tyr) has been reported at this position, which has been classified as likely pathogenic by Clingen platelet VCEP. Therefore, PM5_supporting applied.

PM2_Supporting

This variant is absent from large population databases including gnomAD, ExAC, 1000Genomes

Curation History

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