Submissions for variant NM_000212.3(ITGB3):c.665T>C (p.Leu222Pro)

gnomAD frequency: 0.00001  dbSNP: rs79208797

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen	RCV001290457	SCV001478491	pathogenic	Glanzmann thrombasthenia	2020-11-10	reviewed by expert panel	curation	NM_000212.3(ITGB3):c.665T>C (p.Leu222Pro) is a missense variant which has been previously reported in at least two symptomatic individuals who meet the diagnostic criteria for the GT phenotype (PMIDs:25728920, 11897046). This variant is present at an extremely low MAF of 0.000064 in the Non-Finnish European subpopulation in gnomAD. This variant has been predicted to be deleterious by multiple in silico tools (REVEL score = 0.97). This variant has been reported to occur in the homozygous state in one proband as well as in heterozygous state with another pathogenic variant (p.Cys624Tyr) in a non related proband. Functional studies have demonstrated a deleterious effect on the gene product, preventing the binding of soluble fibrinogen and fibrinogen mimetic antibodies (PMID: 11776310). This variant meets GT specific criteria for PS3, PP4_strong, PM2_supporting, PP3 and PM3_supporting and is therefore classified as Pathogenic.
Invitae	RCV003558796	SCV004298255	pathogenic	not provided	2023-11-10	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 222 of the ITGB3 protein (p.Leu222Pro). This variant is present in population databases (rs79208797, gnomAD 0.002%). This missense change has been observed in individual(s) with autosomal recessive Glanzmann thrombasthenia (PMID: 20020534, 20438394, 25539746). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as p.Leu196Pro. ClinVar contains an entry for this variant (Variation ID: 996163). 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) performed at Invitae indicates that this missense variant is expected to disrupt ITGB3 protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.
ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	RCV002254211	SCV002525469	likely pathogenic	Glanzmann thrombasthenia 1		no assertion criteria provided	research