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.917A>C

CA291224999

1330311 (ClinVar)

Gene: ITGB3 (HGNC:3690)

Condition: Glanzmann thrombasthenia (MONDO:0100326)

Inheritance Mode: Autosomal recessive inheritance

UUID: f08e6a42-0ec0-4b19-b3c0-aa60a34f007f

Approved on: 2024-11-07

Published on: 2024-11-07

HGVS expressions

NM_000212.3:c.917A>C

NC_000017.11:g.47287209A>C

CM000679.2:g.47287209A>C

NC_000017.10:g.45364575A>C

CM000679.1:g.45364575A>C

NC_000017.9:g.42719574A>C

NG_008332.2:g.38368A>C

ENST00000696963.1:c.917A>C

ENST00000559488.7:c.917A>C

ENST00000559488.5:c.917A>C

ENST00000560629.1:c.882A>C

ENST00000571680.1:c.917A>C

NM_000212.2:c.917A>C

Likely Pathogenic

PS3_Moderate PP4_Moderate PM3_Strong

BS1 PM2 PP3

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

PDF

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Platelet Disorders VCEP

The NM_000212.3(ITGB3):c.917A>C (p.His306Pro) missense variant has been reported in at least six GT probands, including two homozygotes (Osaka-5 of PMID: 11806996; patient NT of PMID: 9790984) and four compound heterozygotes (PMIDs: 34066320, 15634267, 9790984). Contributing to this classification is patient TK of PMID: 9790984, who is compound heterozygous for the maternal His306Pro variant and the paternal Gly605Ser (classified Likely Pathogenic by the PD-EP) variant. (PM3_Strong). At least three patients (Patients TK, NT, and HJ in PMID:9790984) with this variant displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia (PP4_moderate). Additionally, αIIbβ3 surface expression was reduced to 19.9%, 7.5% and15.4% respectively, as measured by flow cytometry. Similarly, surface expression of αIIbβ3 measured by flow cytometry in 293 cells transiently co-transfected with His306Pro variant β3 and wild type αIIb showed decreased expression at 25% indicating that this variant impacts protein function (PMID: 11806996; PS3_moderate). 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: PS3_moderate, PM3_strong, PP4_moderate.

PS3_Moderate

Surface expression of αIIbβ3 measured by flow cytometry in 293 cells transiently co-transfected with His306Pro variant β3 and wild type αIIb showed decreased expression at slightly above 25% indicating that this variant impacts protein function (PMID: 11806996).

PP4_Moderate

At least three patients (Patients TK, NT, and HJ in PMID:9790984) with this variant displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia (PP4_moderate). Additionally, αIIbβ3 surface expression was reduced to 19.9%, 7.5% and15.4% respectively, as measured by flow cytometry. However, ITGA2B and ITGB3 were not reported to be sequenced across all exons and intron/exon boundaries.

PM3_Strong

At least six GT probands have been reported with this variant, including two homozygotes (Osaka-5 of PMID: 11806996; patient NT of PMID: 9790984) and four compound heterozygotes (PMIDs: 34066320, 15634267, 9790984). Contributing to this classification is patient TK of PMID: 9790984, who is compound heterozygous for the maternal His306Pro variant and the paternal Gly605Ser (classified Likely Pathogenic by the PD-EP) variant. (PM3_Strong) Though this variant does not meet the PM2_supporting threshold, the PD VCEP deemed this number of patients to be significant and found that being below BS1 was sufficient.

BS1

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

PM2

The highest population minor allele frequency in gnomAD v4.1 is 0.0003564 (16/44888 alleles) in the East Asian population. This intermediate allele frequency is lower than the ClinGen PD VCEP threshold (>0.00158) for BS1 but higher than the threshold (<0.0001) for PM2_Supporting.

PP3

The computational predictor REVEL gives a score of 0.676, which is below the ClinGen PD VCEP PP3 threshold of >0.7 and does not predict a damaging effect on function. And the computational splicing predictor SpliceAI indicated that the variant has no impact on splicing.

Curation History

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