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.760C>A

CA400023674

996175 (ClinVar)

Gene: ITGB3

Condition: Glanzmann thrombasthenia

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 843b4fec-a11b-4e37-908a-d4ecf8c3b472

HGVS expressions

NM_000212.3:c.760C>A

NC_000017.11:g.47286405C>A

CM000679.2:g.47286405C>A

NC_000017.10:g.45363771C>A

CM000679.1:g.45363771C>A

NC_000017.9:g.42718770C>A

NG_008332.2:g.37564C>A

ENST00000559488.7:c.760C>A

ENST00000559488.5:c.760C>A

ENST00000560629.1:c.725C>A

ENST00000571680.1:c.760C>A

NM_000212.2:c.760C>A

NM_000212.3(ITGB3):c.760C>A (p.Gln254Lys)

Likely Pathogenic

PP1 PP3 PM3 PP4_Moderate PM2_Supporting

PM5

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.760C>A (p.Gln254Lys) missense variant is reported in at least 1 compound heterozygous GT proband as well as one additional affected family member (PMID: 31088191; PP1_supporting), with the likely pathogenic variant Cys549Ser (PM3). Proband 2 of PMID: 31088191 was a 6-year-old girl diagnosed with recurrent hematemesis at age 2. Platelet aggregation was absent or defective upon stimulation with physiological stimuli like AA and ADP, but platelets agglutinated near normal in response to ristocetin. Flow cytometric studies found reduced expression of αIIbβ3. Together this is highly specific for Glanzmann thrombasthenia (PP4_Moderate) It is absent from all population databases, including gnomAD (PM2_Supporting) and is predicted damaging by in-silico tools (REVEL score of 0.972; PP3). In summary, this variant meets criteria to be classified as Likely Pathogenic for GT. GT-specific criteria applied: PM2_Supporting, PM3, PP1, PP3, and PP4_Moderate.

PP1

Co-segregation of compound heterozygous genotype Cys549Ser and Gln254Lys with disease was observed in the proband and one affected sibling (PMID: 31088191).

PP3

REVEL score of 0.972 is above the >.0.7 threshold, in support of a deleterious effect.

PM3

Proband 2 of PMID: 31088191 is compound heterozygous for the paternal Cys549Ser (classified Likely Pathogenic by the PD-VCEP) and maternal Gln254Lys variants. 1pt

PP4_Moderate

Proband 2 of PMID: 31088191 was a 6-year-old girl diagnosed with recurrent hematemesis at age 2. Platelet aggregation was absent or defective upon stimulation with physiological stimuli like AA and ADP, but platelets agglutinated near normal in response to ristocetin. Flow cytometric studies found reduced expression of αIIbβ3.

PM2_Supporting

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

PM5

The additional variant Gln254Arg has also been identified at this amino acid residue. Gln254Arg has been classified as VUS by the PD-VCEP. Not considered here to avoid circularity.

Approved on: 2023-12-19

Published on: 2023-12-19

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