Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000235628 | SCV000293399 | pathogenic | not provided | 2016-03-02 | criteria provided, single submitter | clinical testing | The W514R pathogenic variant has been previously reported in multiple individuals with laminopathy, specifically LGMD1B (Astejada et al.,2007; LMNA UMD). Functional studies have demonstrated that W514R leads to abnormal protein function and aggregation (Dialynas et al., 2012). The W514R variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Another nucleotide substitution, c.1540T>A that also results in W514R, was previously reported as a de novo change in an individual with a myopathic gait and proximal weakness in early childhood (Tan et al., 2015). Missense variants in nearby residues (L512P, K515E) have been reported in the Human Gene Mutation Database in association with LMNA-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. The W514R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, the presence of W514R is consistent with a diagnosis of a LMNA-related disorder |