Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV001580247 | SCV001809886 | likely pathogenic | Glanzmann thrombasthenia | 2024-02-20 | reviewed by expert panel | curation | NM_000212.3(ITGB3):c.1031A>C (p.Tyr344Ser) is a missense variant reported in at least one homozygous individual (PM3_supporting) previously who satisfies clinical and laboratory phenotype for GT. Patient GT23 had a history of significant mucocutaneous bleeding, platelet aggregation was absent with three physiological agonists (but normal aggregation with ristocetin) and reduced (<5%) surface expression of αIIbβ3 demonstrated by flowcytometry (PMID: 25728920; PP4_Strong). This variant is predicted deleterious with a REVEL score = 0.982 , which is well above the threshold of >0.70 (PP3). The highest population minor allele frequency in gnomADv4.0 is 0.000003602 (4/1,110,630 alleles) in the European (non-Finnish) population, which is lower than the ClinGen PD VCEP threshold (<0.0001; PM2_Supporting). In summary, this variant meets criteria for PP4_strong, PM2_supporting, PM3_supporting and PP3 and is therefore classified as Likely pathogenic for Glanzmann thrombasthenia. |
| Labcorp Genetics |
RCV002573261 | SCV002983354 | uncertain significance | not provided | 2022-04-09 | criteria provided, single submitter | clinical testing | ClinVar contains an entry for this variant (Variation ID: 1210200). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant disrupts the p.Tyr344 amino acid residue in ITGB3. Other variant(s) that disrupt this residue have been observed in individuals with ITGB3-related conditions (PMID: 19691478, 25728920), which suggests that this may be a clinically significant amino acid residue. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Studies have shown that this missense change alters ITGB3 gene expression (PMID: 25728920). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. This missense change has been observed in individuals with autosomal recessive Glanzmann thrombasthenia (PMID: 22250950, 25728920). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tyrosine, which is neutral and polar, with serine, which is neutral and polar, at codon 344 of the ITGB3 protein (p.Tyr344Ser). |