Submissions for variant NM_000212.3(ITGB3):c.422A>G (p.Tyr141Cys)

dbSNP: rs1739770567

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen	RCV002254817	SCV002525910	likely pathogenic	Glanzmann thrombasthenia	2022-10-06	reviewed by expert panel	curation	The NM_000212.3:c.422A>G variant in ITGB3 is a missense variant predicted to cause substitution of tyrosine by cysteine at amino acid 141 (p.Tyr141Cys). This variant has been observed in compound heterozygosity in one individual (GT53 in PMID: 19691478) in trans (phase confirmed) with ITGB3 variant c.415G>C (p.Asp139His,classified by the Platelet Disorders VCEP as a VUS). This individual displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia (PP4_Moderate). Additionally, GT1-III2, of PMID: 32558238, and patient No.1 of PMID: 15748237, are homozygous for Tyr141Cys (PM3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The variant has been reported to segregate with Glanzmann thrombasthenia (confirmed by bleeding phenotype and platelet aggregometry) in the GT1-III2 proband plus two affected family members, all homozygous for Tyr141Cys genotype. (PP1_moderate; PMID: 32558238). The computational predictor REVEL gives a score of 0.939, which is above the ClinGen Platelet Disorders 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: PM2_Supporting, PP3, PP4_Moderate, PM3, PP1_moderate. (VCEP specifications version 2)
Labcorp Genetics (formerly Invitae), Labcorp	RCV003560900	SCV004298251	pathogenic	not provided	2023-05-22	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 1691482). This variant is also known as Y115C. This missense change has been observed in individuals with autosomal recessive Glanzmann's thrombasthenia (PMID: 15748237, 32558238). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 141 of the ITGB3 protein (p.Tyr141Cys).
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	RCV003987989	SCV004801953	likely pathogenic	Glanzmann thrombasthenia 2	2024-03-26	criteria provided, single submitter	clinical testing	A heterozygous missense variant in exon 4 of the ITGB3 gene that results in the amino acid substitution of Cysteine for Tyrosine at codon 141 was detected . The observed variant lies in the "GGL domain" domain of the ITGB3 protein and has previously been reported in patients affected with Glanzmann thrombasthenia and the observed variant has not been reported in the 1000 genomes, gnomdAD (v2.1) and topmed databases and has a minor allele frequency of 0.00066% and 0.00775% in the gnomAD (v3.1) and our internal databases respectively. The in silico prediction of the variant are probably damaging by PolyPhen-2 (HumDiv) and damaging by SIFT, LRT and MutationTaster2. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as likely pathogenic.