Submissions for variant NM_000212.3(ITGB3):c.565C>T (p.Pro189Ser)

gnomAD frequency: 0.00001  dbSNP: rs958609406

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen	RCV001003533	SCV001397566	pathogenic	Glanzmann thrombasthenia	2020-09-06	reviewed by expert panel	curation	The NM_000212.2:c.565C>T (p.Pro189Ser) missense variant has been reported in at least three homozygotes and two compound heterozygous probands with phenotypes highly specific to GT (PMIDs: 31565851, 25728920, 24236036, 22250950). The variant has been shown to segregate in at least one family with two affected individuals (PMID: 31565851). This variant is at an extremely low frequency with a MAF of 0.00002638 in the South Asian population of gnomAD and multiple lines of computational evidence support a deleterious effect on the gene /gene product (REVEL score of 0.976). Pro189Ser has been expressed in CHO cells and found to have a 94% reduction in surface expression (PMID: 24236036). In summary, based on the available evidence at this time, the variant is classified as Pathogenic. GT-specific criteria applied: PS3_Moderate, PM2_Supporting, PM3_Strong, PP1, PP3, PP4_Strong.
Invitae	RCV003727835	SCV004536447	pathogenic	not provided	2023-08-29	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects ITGB3 function (PMID: 24236036). 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. ClinVar contains an entry for this variant (Variation ID: 812736). This missense change has been observed in individuals with and/or clinical features of autosomal recessive Glanzmann thrombasthenia (PMID: 22250950, 24236036, 25728920, 31565851). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (no rsID available, gnomAD 0.003%). This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 189 of the ITGB3 protein (p.Pro189Ser).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004689952	SCV005185926	pathogenic	Glanzmann thrombasthenia 2	2024-05-03	criteria provided, single submitter	clinical testing	Variant summary: ITGB3 c.565C>T (p.Pro189Ser) results in a non-conservative amino acid change located in the Integrin beta subunit, VWA domain (IPR002369) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251434 control chromosomes (gnomAD). c.565C>T has been reported in the literature in several individuals affected with Glanzmann Thrombasthenia in either the homozygous state or in the compound heterozygous state with pathogenic variants (e.g. Fiore_2012, Laguerre_2013, Nurden_2015, Guillet_2019). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, finding that the variant results in a loss of integrin alphaIIb/beta3 cell surface expression (Laguerre_2013). The following publications have been ascertained in the context of this evaluation (PMID: 22250950, 24236036, 25728920, 31565851). ClinVar contains an entry for this variant (Variation ID: 812736). Based on the evidence outlined above, the variant was classified as pathogenic.
NIHR Bioresource Rare Diseases, University of Cambridge	RCV001003533	SCV001161859	likely pathogenic	Glanzmann thrombasthenia		no assertion criteria provided	research