Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV001768464 | SCV001992217 | uncertain significance | not provided | 2019-04-19 | criteria provided, single submitter | clinical testing | Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge |
Invitae | RCV002540245 | SCV003314142 | uncertain significance | Myofibrillar myopathy 4 | 2022-10-19 | criteria provided, single submitter | clinical testing | 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 1305257). This missense change has been observed in individual(s) with myofibrillar myopathy (PMID: 33308939). This variant is present in population databases (rs778865072, gnomAD 0.003%). This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 26 of the LDB3 protein (p.Pro26Ser). |
Broad Center for Mendelian Genomics, |
RCV002540245 | SCV003761232 | uncertain significance | Myofibrillar myopathy 4 | 2023-01-25 | criteria provided, single submitter | curation | The heterozygous p.Pro26Ser variant in LDB3 was identified by our study in one individual with congenital myopathy. The p.Pro26Ser variant in LDB3 has been previously reported in two siblings with myopathy (PMID: 33308939) but has been identified in 0.003% (1/30616) of South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs778865072). Although this variant has been seen in the general population in a heterozygous state, its frequency is not high enough to rule out a pathogenic role. This variant has also been reported in ClinVar (Variation ID:1305257) and has been interpreted as a variant of uncertain significance by GeneDx. The p.Pro26Ser variant is located in a region of LDB3 that is essential to myofibrillar integrity, suggesting that this variant is in a functional domain and slightly supports pathogenicity ((PMID: 10427098, 15062084). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Pro26Ser variant is uncertain. ACMG/AMP Criteria applied: PM1_Supporting (Richards 2015). |