Submissions for variant NM_000419.5(ITGA2B):c.457G>A (p.Ala153Thr)

gnomAD frequency: 0.00014  dbSNP: rs199641871

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen	RCV002535708	SCV003915996	uncertain significance	Glanzmann thrombasthenia	2023-03-21	reviewed by expert panel	curation	The NM_000419.5:c.457G>A variant in ITGA2B is a missense variant predicted to cause substitution of Alanine by Threonine at amino acid 153 (p.Ala153Thr). This variant is listed in LOVD and reported in ClinVar in an Iranian female but has not been reported in the literature in association with Glanzmann thrombasthenia. No ACMG codes could be applied to this variant under the PD VCEP rules. In summary, this variant meets the criteria to be classified as Uncertain significance - insufficient evidence for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP (VCEP specifications version 2).
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000784902	SCV000923442	uncertain significance	not specified	2019-01-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV002535708	SCV003291212	uncertain significance	Glanzmann thrombasthenia	2023-09-17	criteria provided, single submitter	clinical testing	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. 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. ClinVar contains an entry for this variant (Variation ID: 634433). This variant has not been reported in the literature in individuals affected with ITGA2B-related conditions. This variant is present in population databases (rs199641871, gnomAD 0.02%). This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 153 of the ITGA2B protein (p.Ala153Thr).
Ambry Genetics	RCV002535709	SCV003744542	uncertain significance	Inborn genetic diseases	2022-12-02	criteria provided, single submitter	clinical testing	The c.457G>A (p.A153T) alteration is located in exon 4 (coding exon 4) of the ITGA2B gene. This alteration results from a G to A substitution at nucleotide position 457, causing the alanine (A) at amino acid position 153 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
PreventionGenetics, part of Exact Sciences	RCV004549860	SCV004120951	uncertain significance	ITGA2B-related disorder	2023-04-27	criteria provided, single submitter	clinical testing	The ITGA2B c.457G>A variant is predicted to result in the amino acid substitution p.Ala153Thr. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.023% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-42463036-C-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
CeGaT Center for Human Genetics Tuebingen	RCV003413576	SCV004140681	uncertain significance	not provided	2023-10-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000784902	SCV005202984	uncertain significance	not specified	2024-07-22	criteria provided, single submitter	clinical testing	Variant summary: ITGA2B c.457G>A (p.Ala153Thr) results in a non-conservative amino acid change in 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 0.00014 in 249070 control chromosomes (gnomAD). To our knowledge, no occurrence of c.457G>A in individuals affected with ITGA2B-Related Disorders and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 634433). Based on the evidence outlined above, the variant was classified as uncertain significance.