Submissions for variant NM_000419.5(ITGA2B):c.1787T>C (p.Ile596Thr)

gnomAD frequency: 0.00006  dbSNP: rs76811038

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen	RCV000003034	SCV001397508	pathogenic	Glanzmann thrombasthenia	2023-11-17	reviewed by expert panel	curation	The NM_000419.5(ITGA2B):c.1787T>C (p.Ile596Thr) missense variant has been reported in the homozygous state in at least 2 apparently unrelated individuals (PMID: 22513797, 20020534) and in the compound heterozygous state in 4 individuals (PMID: 9215749, 9734640, 34552732, 25373348). The second variants in these patients are c.3060+2T>C (classified Pathogenic by the PD-VCEP; without confirmation of trans phase), Glu355Lys (classified Pathogenic by the PD-VCEP; with confirmation of trans phase), c.2841+1G>T, and c.408G>C (latter two not considered here to avoid circularity) respectively (PM3_Strong). The proband from PMID: 22513797 meets criteria for PP4_Strong including mucocutaneous bleeding; abnormal platelet aggregometry in response to at least 2 agonist and normal response to ristocetin; absent surface expression of GPIIb-IIIa on flow cytometry; and full sequencing of ITGA2B and ITGB3. It was found to co-segregate with disease in 1 additional family member (PP1). Ile596Thr is reported in gnomAD v4.0.0 at a frequency of 0.00008305 (98/1179968 alleles) in the non-Finnish European population, below the PM2_supporting threshold of <0.0001. In summary, this variant is classified Pathogenic for autosomal recessive Glanzmann thrombasthenia. GT-specific codes applied: PP4_Strong, PM2_Supporting, PM3_Strong, PP1. (PD-VCEP specifications version 2)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000003034	SCV003280192	pathogenic	Glanzmann thrombasthenia	2022-07-04	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 2900). This missense change has been observed in individuals with clinical features of Glanzmann thrombasthenia (PMID: 9215749, 9734640, 20020534, 22513797, 25326637, 25373348). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs76811038, gnomAD 0.01%). This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 596 of the ITGA2B protein (p.Ile596Thr). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0").
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001580160	SCV004020609	likely pathogenic	Glanzmann thrombasthenia 1	2023-06-02	criteria provided, single submitter	clinical testing	Variant summary: ITGA2B c.1787T>C (p.Ile596Thr) results in a non-conservative amino acid change located in the Integrin alpha-2 domain (IPR013649) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.4e-05 in 250706 control chromosomes (gnomAD). c.1787T>C has been reported in the literature as a biallelic genotype in individuals affected with Glanzmann thrombasthenia 1 (e.g. French_1997, Ruan_1998, Jallu_2010) and in one potential compound heterozygote (e.g. Lee_2014). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 9215749, 20020534, 25326637, 9734640). Two ClinVar submitters have assessed the variant since 2014, including one expert panel (ClinGen Platelet Disorders Variant Curation Expert Panel): the expert panel classified the variant as uncertain significance, and the other submitter classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
OMIM	RCV001580160	SCV000023192	pathogenic	Glanzmann thrombasthenia 1	1998-09-01	no assertion criteria provided	literature only
PreventionGenetics, part of Exact Sciences	RCV004737134	SCV005361672	likely pathogenic	ITGA2B-related disorder	2024-07-02	no assertion criteria provided	clinical testing	The ITGA2B c.1787T>C variant is predicted to result in the amino acid substitution p.Ile596Thr. This variant has been reported in the compound heterozygous state and homozygous states in two patients with Glanzmann’s thrombasthenia (French et al. 1997. PubMed ID: 9215749). This variant is reported in 0.013% of alleles in individuals of European (Non-Finnish) descent in gnomAD and is interpreted as pathogenic by the ClinGen Platelet Disorders Variant Curation Expert Panel (https://www.ncbi.nlm.nih.gov/clinvar/variation/2900/). We interpret this variant as likely pathogenic.