Submissions for variant NM_000419.5(ITGA2B):c.2915_2916delinsT (p.Pro972fs)

dbSNP: rs2048523750

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen	RCV001246994	SCV001809905	uncertain significance	Glanzmann thrombasthenia	2024-06-06	reviewed by expert panel	curation	The NM_000419.5(ITGA2B):c.2915_2916delinsT (p.Pro972fs) variant causes a frameshift and subsequent stop loss, resulting in alteration of the remaining 68 amino acids followed by the addition of 90 amino acids to the ITGA2B protein. This alters the transmembrane domain of the protein which is considered a critical region for protein function by the Platelet Disorders VCEP (PVS1_strong). This variant is absent from gnomAD v4.0 (PM2_Supporting). In summary, this variant is classified as uncertain significance for autosomal recessive Glanzmann thrombasthenia. GT-specific criteria applied: PVS1_Strong, PM2_Supporting.
Invitae	RCV001246994	SCV001420389	pathogenic	Glanzmann thrombasthenia	2019-09-21	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the C-terminus of the ITGA2B protein. Other variant(s) that disrupt this region (p.Leu973Alafs*63) have been determined to be pathogenic (PMID: 28888044). This suggests that variants that disrupt this region of the protein are likely to be causative of disease. This variant has not been reported in the literature in individuals with ITGA2B-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change results in a frameshift in the ITGA2B gene (p.Pro972Leufs*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 68 amino acids of the ITGA2B protein and extend the protein by an unknown number of additional amino acids.