Submissions for variant NM_000419.5(ITGA2B):c.1234G>A (p.Gly412Arg)

dbSNP: rs780786843

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen	RCV001225257	SCV001397518	pathogenic	Glanzmann thrombasthenia	2021-11-03	reviewed by expert panel	curation	The c.1234G>A (p.Gly412Arg) variant has been reported in at least six GT patients in the literature; at least 4 of them (from PMIDs: 29675921, 24418945, 19691478, 21557682) with a phenotype highly specific to GT. This includes 2 homozygotes and 4 compound heterozygotes. The variant is found at an extremely low frequency, with an the overall allele frequency on gnomAD is 0.00010 (5/49256) alleles in the Latino population). Multiple lines of computational evidence support a deleterious effect on the gene/gene product; HumanSplicingFinder and MaxEntScan agree that there is activation of an exonic cryptic acceptor site with potential alteration of splicing. In summary, this variant meets criteria to be classified as Pathogenic for GT. GT-specific criteria applied: PM3_Strong, PM2_Supporting, and PP4_Strong.
GeneDx	RCV000425256	SCV000521350	uncertain significance	not provided	2019-05-21	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors, splice predictors, and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 19172520, 11798398, 21557682, 19691478, 25275492, 29675921, 32237906)
PreventionGenetics, part of Exact Sciences	RCV004551447	SCV004120512	pathogenic	ITGA2B-related disorder	2023-03-22	criteria provided, single submitter	clinical testing	The ITGA2B c.1234G>A variant is predicted to result in the amino acid substitution p.Gly412Arg. This variant is also described using legacy nomenclature as p.Gly381Arg, has been reported in homozygous and compound heterozygous states in multiple individuals with Glanzmann’s Thrombasthenia (Vinciguerra et al. 2001. PubMed ID: 11798398; Kannan et al. 2009. PubMed ID: 19691478; Nurden et al. 2011. PubMed ID: 21557682; Zhou et al. 2018. PubMed ID: 29675921. Table S2). This variant is reported in 0.015% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-42458406-C-T). This variant is interpreted as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001225257	SCV004298234	likely pathogenic	Glanzmann thrombasthenia	2022-12-05	criteria provided, single submitter	clinical testing	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ITGA2B protein function. ClinVar contains an entry for this variant (Variation ID: 381748). This variant is also known as p.Gly381Arg. This missense change has been observed in individuals with Glanzmann’s thrombasthenia (PMID: 11798398, 19691478, 21557682, 29675921). This variant is present in population databases (rs780786843, gnomAD 0.01%). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 412 of the ITGA2B protein (p.Gly412Arg).
ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	RCV002244886	SCV002515504	pathogenic	Glanzmann thrombasthenia 1		no assertion criteria provided	clinical testing