Submissions for variant NM_000212.3(ITGB3):c.718C>T (p.Arg240Trp)

gnomAD frequency: 0.00001  dbSNP: rs121918446

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen	RCV001580253	SCV001809897	likely pathogenic	Glanzmann thrombasthenia	2024-08-20	reviewed by expert panel	curation	The NM_000212.2(ITGB3):c.718C>T (p.Arg240Trp) missense variant has been reported in at least five patients (PMID: 32200672, 7509233, 1602006, doi.org/10.2491/jjsth.10.243, and a thesis by Zapelli in 2014) with a phenotype highly specific to GT. Several probands from PMID: 32200672, PMID: 7509233, and PMID: 1602006 are homozygous (PM3) and meet the criteria for PP4_moderate; including mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin. Additionally, surface αIIbβ3 was dysfunctional as shown by defective PAC-1 and fibrinogen binding. This variant is at an extremely low frequency (below the <1/10,000 threshold) with a MAF of 0.00002196 (2/91,084 alleles) in the gnomADv4.1.0 South Asian population (PM2_supporting). It is predicted to have a deleterious effect (REVEL score 0.832; PP3) and occurs at the same residue as pathogenic variant Arg240Gln (PM5). In summary this variant meets criteria to be classified as likely pathogenic for GT. GT-specific criteria applied: PM2_Supporting, PM3, PM5, PP3, and PP4_Moderate.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002513046	SCV003451496	pathogenic	not provided	2023-12-22	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 240 of the ITGB3 protein (p.Arg240Trp). This variant is present in population databases (rs121918446, gnomAD 0.006%). This missense change has been observed in individuals with autosomal recessive Glanzmann thrombasthenia (PMID: 1602006, 9215749, 32757236; Invitae). This variant is also known as p.Arg214Trp. ClinVar contains an entry for this variant (Variation ID: 13555). 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%. Experimental studies have shown that this missense change affects ITGB3 function (PMID: 9050889). This variant disrupts the p.Arg240 amino acid residue in ITGB3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1371279, 9215749, 30138987). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000014514	SCV004020499	pathogenic	Glanzmann thrombasthenia 2	2023-06-20	criteria provided, single submitter	clinical testing	Variant summary: ITGB3 c.718C>T (p.Arg240Trp) 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 249030 control chromosomes (gnomAD). Another variant at the same amino acid position (p.Arg240Gln) has been classified as pathogenic in ClinVar, providing supporting evidence for R240 as a clinically significant amino acid. c.718C>T has been reported in the literature in at least one homozygous individual affected with Glanzmann Thrombasthenia 2 (example: Lanza_1992) and as a milder phenotype in heterozygous individuals, including individuals affected with isolated nonsyndromic thrombocytopenia or other clinical features of Glanzmann Thrombasthenia 2 (examples: Gueguen_2020, Lanza_1992). These data indicate that the variant is likely to be associated with disease. One publication reports experimental evidence evaluating an impact on protein function, suggesting the variant causes defective ligand binding (Baker_1997), however, does not allow convincing conclusions about the variant effect. Another publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 2-4% of WT levels fibrinogen binding/platelet adhesion in a patient with a homozygous genotype. The following publications have been ascertained in the context of this evaluation (PMID: 9050889, 32757236, 1602006). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV001580253	SCV004848913	pathogenic	Glanzmann thrombasthenia	2023-02-02	criteria provided, single submitter	clinical testing	The p.Arg240Trp variant in ITGB3 has been reported in 3 homozygous individuals with Glanzmann thrombasthenia (Lanza 1992 PMID: 1602006, Paciullo 2021 PMID: 32200672, Djaffar 1993 PMID: 7509233). It was also identified 0.001% (1/68038) of European chromosomes by gnomAD, v.3 (http://gnomad.broadinstitute.org). The variant is also reported in ClinVar, and has been classified as pathogenic by the ClinGen Platelet Disorders Variant Curation Expert Panel (Variation ID 13555). In vitro analysis using patient derived platelets support an impact to normal protein function. Computational prediction tools and conservation analysis suggest that this variant may impact the protein. Another variant involving this codon (p.Arg240Gln) has been identified in individuals with Glanzmann thrombasthenia and is classified as pathogenic by the ClinGen Platelet Disorders Variant Curation Expert Panel. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Glanzmann thrombasthenia. ACMG/AMP criteria applied: PM3, PM5, PS3_Supporting, PM2_Supporting, PP3, PP4.
OMIM	RCV000014514	SCV000034765	pathogenic	Glanzmann thrombasthenia 2	1992-06-01	no assertion criteria provided	literature only
ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	RCV002243643	SCV002515561	likely pathogenic	Glanzmann thrombasthenia 1		no assertion criteria provided	clinical testing