Submissions for variant NM_000419.5(ITGA2B):c.1627C>T (p.Arg543Trp)

gnomAD frequency: 0.00277  dbSNP: rs143967758

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen	RCV000312553	SCV001397504	benign	Glanzmann thrombasthenia	2020-06-04	reviewed by expert panel	curation	The NM_000419.5:c.1627C>T (p.Arg543Trp) variant occurs at an allele frequency of 0.00968 in the gnomAD African population and is predicted by REVEL score of 0.229 to have no impact. In summary, the variant is classified as benign. GT-specific criteria applied: BA1 and BP4.
Illumina Laboratory Services, Illumina	RCV000312553	SCV000403373	likely benign	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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000312553	SCV001004212	benign	Glanzmann thrombasthenia	2024-01-22	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV001820972	SCV002072058	uncertain significance	not specified	2020-06-10	criteria provided, single submitter	clinical testing	DNA sequence analysis of the ITGA2B gene demonstrated a sequence change, c.1627C>T, in exon 17 that results in an amino acid change, p.Arg543Trp. This sequence change does not appear to have been previously described in patients with ITGA2B-related disorders and has been described in the gnomAD database with a relatively high frequency of 0.97% in the African sub-population (dbSNP rs143967758). The p.Arg543Trp change affects a poorly conserved amino acid residue located in a domain of the ITGA2B protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Arg543Trp substitution. Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Arg543Trp change remains unknown at this time.
PreventionGenetics, part of Exact Sciences	RCV004549706	SCV004755166	likely benign	ITGA2B-related disorder	2019-06-28	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).