Submissions for variant NM_000419.5(ITGA2B):c.3092_3093dup (p.Glu1032fs)

dbSNP: rs2048504826

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen	RCV001225252	SCV001397509	uncertain significance	Glanzmann thrombasthenia	2023-06-01	reviewed by expert panel	curation	The NM_000419.5(ITGA2B):c.3092_3093dup variant results in a frameshift, p.Glu1032TrpfsTer98, and introduction of a stop codon further than the original. This adds 90 amino acids to the ITGA2B protein. The variant is absent from population databases, including gnomADv2.1.1 (PM2_supporting). It is reported in a compound heterozygous individual with the c.3060+2T>C variant (classified Pathogenic by the PD VCEP; PM3_supporting); however, the individual does not meet criteria for PP4 (PMID: 9215749). In summary, this variant meets the criteria to be classified as uncertain significance for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PM2_Supporting, BP4 (PD VCEP specifications version 2.1).
Labcorp Genetics (formerly Invitae), Labcorp	RCV001225252	SCV001421617	uncertain significance	Glanzmann thrombasthenia	2023-01-17	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. This variant disrupts the C-terminus of the ITGA2B protein. Other variant(s) that disrupt this region (p.*1040Trpext*) have been observed in individuals with ITGA2B-related conditions (PMID: 19691478). This suggests that this may be a clinically significant region of the protein. ClinVar contains an entry for this variant (Variation ID: 953020). This variant is also known as 3094insTG. This frameshift has been observed in individual(s) with Glanzmann Thrombasthenia (PMID: 9215749). This variant is not present in population databases (gnomAD no frequency). This sequence change results in a frameshift in the ITGA2B gene (p.Glu1032Trpfs*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 9 amino acids of the ITGA2B protein and extend the protein.
ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	RCV002245884	SCV002515508	pathogenic	Platelet-type bleeding disorder 16		no assertion criteria provided	research