Submissions for variant NM_000212.3(ITGB3):c.392G>C (p.Arg131Pro)

dbSNP: rs201806801

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen	RCV001580244	SCV001809883	likely pathogenic	Glanzmann thrombasthenia	2024-08-20	reviewed by expert panel	curation	NM_000212.3(ITGB3):c.392G>C (p.Arg131Pro) is a rare missense variant; the highest population minor allele frequency in gnomAD v4.0 is 0.00001334 (1/74978 alleles) in the African/African American population, which is lower than the ClinGen PD VCEP threshold (<0.0001; PM2_Supporting). In silico tools (REVEL score =0.929) predict this variant to have a deleterious effect on the gene product (PP3). It has been reported in at least one proband with a GT specific clinical and laboratory phenotype (PMID: 25728920). Proband GT35a had significant mucocutaneous bleeding. Aggregometry shows lack of platelet aggregation with physiological agonists except ristocetin and flow cytometry demonstrated reduced (<5%) surface expression of αIIbβ3 (PP4_Strong). Sanger sequencing ensured full coverage of all exons, splice sites and UTRs of IGTB3 and ITGA2B genes. The variant segregated in the proband (GT35a) plus one affected relative (sister - GT35b) in PMID 25728920 (PP1). In both the proband and affected relative it was reported to occur in the compound heterozygous state with a splice variant (c.777+1G>A) which has been classified as Pathogenic by the ClinGen Platelet Disorders VCEP but is not sufficiently rare to consider applying PM3. One homozygous GT patient (0.5pt) has been identified at Versiti (PM3_supporting). This variant meets GT specific criteria for PP4_strong, PP3, PP1, PM2_supporting, PM3_supporting and is therefore classified as Likely Pathogenic for autosomal recessive Glanzmann thrombasthenia.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003546709	SCV004266675	likely pathogenic	not provided	2023-11-14	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 131 of the ITGB3 protein (p.Arg131Pro). This variant is present in population databases (rs201806801, gnomAD 0.007%). This missense change has been observed in individuals with Glanzmann thrombasthenia (PMID: 23300803, 25728920; external communication). ClinVar contains an entry for this variant (Variation ID: 1210198). 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%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.