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.1388G>C

CA400029054

1691487 (ClinVar)

Gene: ITGB3 (HGNC:3690)

Condition: Glanzmann thrombasthenia (MONDO:0100326)

Inheritance Mode: Autosomal recessive inheritance

UUID: dbb0136b-f516-4fb1-9771-b243432556e2

Approved on: 2025-03-06

Published on: 2025-03-06

HGVS expressions

NM_000212.3:c.1388G>C

NC_000017.11:g.47292266G>C

CM000679.2:g.47292266G>C

NC_000017.10:g.45369632G>C

CM000679.1:g.45369632G>C

NC_000017.9:g.42724631G>C

NG_008332.2:g.43425G>C

ENST00000696963.1:c.1388G>C

ENST00000559488.7:c.1388G>C

ENST00000559488.5:c.1388G>C

ENST00000560629.1:c.1353G>C

NM_000212.2:c.1388G>C

Likely Pathogenic

PM3_Supporting PP1 PP3 PP4_Strong PM2_Supporting

PS3

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_000212.3(ITGB3):c.1388G>C (p.Cys463Ser) missense variant has been observed in at least one GT patient (Patient 7 in PMID: 34267460), whom displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia. Additionally, αIIbβ3 surface expression was reduced to 0.5-1.7%, as measured by flow cytometry (PP4_strong). The variant was been reported to segregate with Glanzmann thrombasthenia in Patient 7 plus one affected family member, both with the homozygous Cys463Ser genotype. (PM3_supporting, PP1; PMID: 34267460). The highest population minor allele frequency in gnomAD v4.1 is 0.00001098 (1/91078 alleles) in the South Asian genetic ancestry group, which is lower than the ClinGen PD VCEP threshold (<0.0001; PM2_Supporting). The computational predictor REVEL gives a score of 0.898, which is above the ClinGen PD VCEP threshold of >0.7 and predicts a damaging effect on function (PP3). In summary this variant meets criteria to be classified as Likely Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PP4_strong, PP1, PP3, PM2_supporting, PM3_supporting. (VCEP specifications version 2.1)

PM3_Supporting

Patient 7 of PMID: 34267460 is homozygous for this variant (0.5pt; PM3_supporting).

PP1

The variant has been reported to segregate with Glanzmann thrombasthenia in the proband plus one affected family member, both with the homozygous Cys463Ser genotype. (PP1; PMID: 34267460).

PP3

The computational predictor REVEL gives a score of 0.898, which is above the ClinGen PD VCEP threshold of >0.7 and predicts a damaging effect on function (PP3).

PP4_Strong

At least one patient (Patient 7 in PMID34267460) with this variant displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia. Additionally, αIIbβ3 surface expression was reduced to 0.5-1.7%, as measured by flow cytometry. ITGA2B and ITGB3 were sequenced across all exons and intron/exon boundaries. (PP4_strong)

PM2_Supporting

The highest population minor allele frequency in gnomAD v4.1 is 0.00001098 (1/91078 alleles) in the South Asian genetic ancestry group, which is lower than the ClinGen PD VCEP threshold (<0.0001; PM2_Supporting).

PS3

Surface expression of αIIbβ3 measured by flow cytometry in BHK cells transiently co-transfected with Cys463Ser (here referred to as Cys437Ser) variant β3 and wild type αIIb showed decreased expression at 40% WT levels of positive cells. This modest reduction is insufficient to apply PS3 (PMID: 22308022).

Curation History

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