Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV001803404 | SCV002047553 | likely pathogenic | Glanzmann thrombasthenia | 2021-12-21 | reviewed by expert panel | curation | The NM_000212.3(ITGB3):c.917A>C (p.His306Pro) missense variant has been reported in at least six GT probands, including two homozygotes (Osaka-5 of PMID: 11806996; patient NT of PMID: 9790984) and four compound heterozygotes (PMIDs: 34066320, 15634267, 9790984). Contributing to this classification is patient TK of PMID: 9790984, who is compound heterozygous for the maternal His306Pro variant and the paternal Gly605Ser (classified Likely Pathogenic by the PD-EP) variant. (PM3_Strong). At least three patients (Patients TK, NT, and HJ in PMID:9790984) with this variant displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia (PP4_moderate). Additionally, αIIbβ3 surface expression was reduced to 19.9%, 7.5% and15.4% respectively, as measured by flow cytometry. Similarly, surface expression of αIIbβ3 measured by flow cytometry in 293 cells transiently co-transfected with His306Pro variant β3 and wild type αIIb showed decreased expression at 25% indicating that this variant impacts protein function (PMID: 11806996; PS3_moderate). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00005437 (1/18392 alleles) in the East Asian population, which is lower than the ClinGen PD VCEP threshold (<0.0001; PM2_Supporting). In summary this variant meets criteria to be classified as Likely Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PS3_moderate, PM2_supporting, PM3_strong, PP4_moderate. (VCEP specifications version 2; date of approval 12/21/2021) |
| Labcorp Genetics |
RCV003560851 | SCV004298260 | pathogenic | not provided | 2023-05-09 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. 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: 1330311). This variant is also known as H280P. This missense change has been observed in individuals with Glanzmann thrombasthenia (PMID: 9790984, 34066320). This variant is present in population databases (rs13306476, gnomAD 0.006%). This sequence change replaces histidine, which is basic and polar, with proline, which is neutral and non-polar, at codon 306 of the ITGB3 protein (p.His306Pro). |