Submissions for variant NM_000419.5(ITGA2B):c.2363C>A (p.Ala788Asp)

gnomAD frequency: 0.00021  dbSNP: rs142445733

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen	RCV000290064	SCV004190239	uncertain significance	Glanzmann thrombasthenia	2023-11-02	reviewed by expert panel	curation	The c.2363C>A variant in ITGA2B is a missense variant predicted to cause substitution of Alanine by Aspartic Acid at amino acid 788 (p.Ala788Asp). The computational predictor REVEL gives a score of 0.179, which is below the ClinGen PD VCEP threshold of <0.25 and predicts no damaging effect on ITGA2B function (BP4). This variant was observed by Illumina as part of a predisposition screen in an ostensibly healthy population, however, no cases of the variant segregating with Glanzmann thrombasthenia were found in the literature. In summary, this variant meets the criteria to be classified as VUS for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: BP4 (VCEP specifications version 2)
Illumina Laboratory Services, Illumina	RCV000290064	SCV000403364	uncertain significance	Glanzmann thrombasthenia	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000290064	SCV003248274	uncertain significance	Glanzmann thrombasthenia	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 788 of the ITGA2B protein (p.Ala788Asp). This variant is present in population databases (rs142445733, gnomAD 0.08%). This variant has not been reported in the literature in individuals affected with ITGA2B-related conditions. ClinVar contains an entry for this variant (Variation ID: 323546). 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 not expected to disrupt ITGA2B protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Revvity Omics, Revvity	RCV003133221	SCV003815691	uncertain significance	not provided	2023-08-08	criteria provided, single submitter	clinical testing
Centre for Clinical Genetics and Genomic Diagnostics, Zealand University Hospital	RCV003133221	SCV005328413	uncertain significance	not provided	2024-02-06	criteria provided, single submitter	clinical testing