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.1595G>T

CA400029961

1879032 (ClinVar)

Gene: ITGB3 (HGNC:3690)

Condition: Glanzmann thrombasthenia (MONDO:0100326)

Inheritance Mode: Autosomal recessive inheritance

UUID: 1a1de21d-c6a1-42e4-bd6a-fa8b296a1d99

Approved on: 2025-06-19

Published on: 2025-06-19

HGVS expressions

NM_000212.3:c.1595G>T

NC_000017.11:g.47292473G>T

CM000679.2:g.47292473G>T

NC_000017.10:g.45369839G>T

CM000679.1:g.45369839G>T

NC_000017.9:g.42724838G>T

NG_008332.2:g.43632G>T

ENST00000696963.1:c.1595G>T

ENST00000559488.7:c.1595G>T

ENST00000559488.5:c.1595G>T

ENST00000560629.1:c.1560G>T

NM_000212.2:c.1595G>T

Likely Pathogenic

PP3 PM5 PM2_Supporting PP4_Moderate

PM3

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.1595G>T (p.Cys532Phe) missense variant has been reported in at least one patient (Case 10 in PMID: 34066320) who displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia (PP4_moderate). This variant is absent from gnomAD v4.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.965, which is above the ClinGen PD VCEP threshold of >0.7 and predicts a damaging effect on function (PP3). Two different missense variants, Cys532Tyr and Cys532Arg, in the same codon as Cys532Phe, have been classified as likely pathogenic for Glanzmann thrombasthenia by the ClinGen PD VCEP (PM5). In summary, this variant meets the 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: PM2_supporting, PM5, PP3, PP4_moderate.

PP3

The computational predictor REVEL gives a score of 0.965, which is above the ClinGen PD VCEP threshold of >0.7 and predicts a damaging effect on function (PP3).

PM5

Two different missense variants, Cys532Tyr and Cys532Arg, in the same codon as Cys532Phe, have been classified as likely pathogenic for Glanzmann thrombasthenia by the ClinGen PD VCEP (PM5).

PM2_Supporting

This variant is absent from gnomAD v4.1 (PM2_Supporting).

PP4_Moderate

At least one patient (Case 10 in PMID: 34066320) 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 but the value was not provided.

PM3

Case 10 (PMID: 34066320) is compound heterozygous for Cys532Phe and c.1913+5G>T (classified Likely Pathogenic by the PD-EP; does not meet PM2). The variants were confirmed in trans by Sanger sequencing in family 10. 0pt

Curation History

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