Submissions for variant NM_000419.5(ITGA2B):c.2504C>T (p.Pro835Leu)

dbSNP: rs369457651

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen	RCV001122398	SCV004190251	uncertain significance	Glanzmann thrombasthenia	2023-10-17	reviewed by expert panel	curation	The c.2504C>T variant in ITGA2B is a missense variant predicted to cause substitution of Proline by Leucine at amino acid 835 (p.Pro835Leu). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00002900 (1/34480 alleles) in the Latino/Admixed American population, which is lower than the ClinGen PD VCEP threshold (<0.0001; PM2_Supporting). The computational predictor REVEL gives a score of 0.763, which is above the ClinGen PD VCEP threshold of >0.7 and predicts a damaging effect on function (PP3). 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 Uncertain significance - insufficient evidence for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PM2_Supporting and PP3 (VCEP specifications version 2).
Illumina Laboratory Services, Illumina	RCV001122398	SCV001281112	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	RCV001122398	SCV004290946	uncertain significance	Glanzmann thrombasthenia	2023-02-16	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 835 of the ITGA2B protein (p.Pro835Leu). This variant is present in population databases (rs369457651, gnomAD 0.003%). 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: 888825). 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. 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.