Submissions for variant NM_000419.5(ITGA2B):c.1628G>A (p.Arg543Gln)

gnomAD frequency: 0.00011  dbSNP: rs139770734

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen	RCV001128233	SCV005061667	uncertain significance	Glanzmann thrombasthenia	2024-03-07	reviewed by expert panel	curation	The c.1628G>A variant in ITGA2B is a missense variant predicted to cause substitution of Arginine by Glutamine at amino acid 543 (p.Arg543Gln). The computational predictor REVEL gives a score of 0.206, 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, but was not found in the literature in any patient with Glanzmann thrombasthenia. The highest population minor allele frequency in gnomAD v 4.0.0 is 0.0001602 (189/1179970 alleles) in the European (non-Finnish) population. This intermediate allele frequency is lower than the ClinGen PD VCEP threshold (>0.00158) for BS1 but higher than the threshold (<0.0001) for PM2_Supporting. In summary, this variant is classified as uncertain significance based on ACMG/AMP criteria as specified by the PD VCEP: BP4.
Illumina Laboratory Services, Illumina	RCV001128233	SCV001287648	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	RCV001128233	SCV003258391	uncertain significance	Glanzmann thrombasthenia	2022-08-28	criteria provided, single submitter	clinical testing	This variant has not been reported in the literature in individuals affected with ITGA2B-related conditions. 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. 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: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 892303). This variant is present in population databases (rs139770734, gnomAD 0.02%). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 543 of the ITGA2B protein (p.Arg543Gln).