Submissions for variant NM_000419.5(ITGA2B):c.3092del (p.Leu1031fs)

dbSNP: rs2143417444

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen	RCV002254823	SCV002525916	likely pathogenic	Glanzmann thrombasthenia	2021-12-02	reviewed by expert panel	curation	The NM_000419.5(ITGA2B):c.3092del (p.Leu1031ArgfsTer?) variant causes a frameshift and subsequent stop loss. This results in the addition of 90 amino acids to the ITGA2B protein, beyond the cytoplasmic domain (PM4). The variant is absent from gnomAD v2.1.1 (PM2_Supporting). At least one patient (Patient GT11 in PMID:25373348) with this variant displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia. Additionally, alphaIIbbeta3 surface expression was reduced between 5% and 20% and function was pathological, as measured by flow cytometry (PP4_strong). This patient is compound heterozygous for the maternal c.3092del variant and Leu214Pro (classified Pathogenic by the PD-EP), without confirmation of trans phase (PM3_supporting). In summary this variant meets criteria to be classified as Likely Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PP4_strong, PM2_supporting, PM3_supporting, PM4. (VCEP specifications version 2; date of approval xx/xx/xxxx)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004526920	SCV005039769	likely pathogenic	Glanzmann thrombasthenia 1	2024-03-19	criteria provided, single submitter	clinical testing	Variant summary: ITGA2B c.3092delT (p.Leu1031ArgfsX70+) causes a frameshift which results in an extension of the protein. This variant results in the addition of 90 amino acids to the ITGA2B protein, beyond the cytoplasmic domain. The variant was absent in 251356 control chromosomes. c.3092delT has been reported in the literature in at-least two individuals affected with Glanzmann thrombasthenia, in each case, it was at a compound heterozygous along with a different pathogenic missense (example, Sandrock-Lang_2015, Sharma_2021). These data indicate that the variant may be associated with disease. Additionally, a similar extension variant c.3091delC variant causes a frameshift Leu1031TrpfsTer97 and subsequent stop loss, also adds 90 amino acids to the ITGA2B protein, and was evaluated Likely Pathogenic per ClinGen Platelet Disorders Variant Curation Expert Panel (ClinVar ID 1879040). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 25373348, 34267460). ClinVar contains an entry for this variant (Variation ID: 1691488). Based on the evidence outlined above, the variant was classified as likely pathogenic.