ClinVar Miner

Submissions for variant NM_000212.3(ITGB3):c.1199G>A (p.Cys400Tyr)

dbSNP: rs121918449
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen RCV001801833 SCV002047580 pathogenic Glanzmann thrombasthenia 2024-06-06 reviewed by expert panel curation The NM_000212.2(ITGB3):c.1199G>A (p.Cys400Tyr) missense has been identified in at least 4 probands, including GT11 and GT15a of PMID: 29675921 meeting the criteria for PP4_strong; including mucocutaneous bleeding, impaired aggregation with all agonists except ristocetin, and reduced surface expression of αIIbβ3 measured by flow cytometry. ITGA2B and ITGB3 were sequenced across all exons and intron/exon boundaries. Siblings GT15a and GT15b are both compound heterozygous for Cys400Tyr and pathogenic variant c.1525del (PP1; PMID: 29675921) with confirmation of trans phase was reported in PMID: 18788610. Additionally, two homozygous patients have been reported (PMIDs: 8781422, 35198519) (PM3_Strong). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.968, which predicts a damaging effect on ITGB3 function (PP3). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PM2_supporting, PM3_strong, PP1, PP3, PP4_strong. (VCEP specifications version 2; date of approval 06/06/2024)
Labcorp Genetics (formerly Invitae), Labcorp RCV003556015 SCV004298261 pathogenic not provided 2023-04-15 criteria provided, single submitter clinical testing This missense change has been observed in individual(s) with Glanzmann thrombasthenia (PMID: 8781422, 29675921, 35198519). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 400 of the ITGB3 protein (p.Cys400Tyr). This variant is not present in population databases (gnomAD no frequency). This variant is also known as Cys374Tyr. ClinVar contains an entry for this variant (Variation ID: 13562). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ITGB3 protein function. Experimental studies have shown that this missense change affects ITGB3 function (PMID: 8781422). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000014530 SCV000034781 pathogenic Glanzmann thrombasthenia 2 1996-09-01 no assertion criteria provided literature only

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