Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000182372 | SCV000234704 | uncertain significance | not provided | 2017-10-03 | criteria provided, single submitter | clinical testing | The G523R (c.1567G>C) variant of uncertain significance in the LMNA gene has not been published in association with cardiomyopathy to our knowledge. However, a different nucleotide substitution resulting the same amino acid change (c.1567G>A) has previously been reported in association with DCM and LGMD (Millat et al., 2011; Pugh et al., 2014; Haas et al., 2015; Magri et al., 2015). The G523R (c.1567G>C) variant is not observed in large population cohorts (Lek et al., 2016). This 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 within lamin tail domain (LTD) of the LMNA gene at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Other pathogenic or likely pathogenic missense variants in nearby residues (R527C, R527H, T528K, T528R) have been reported in HGMD in association with LMNA-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. However, the G523R (c.1567G>C) variant lacks observation in a significant number of affected individuals, segregation data, and functional evidence, which would further clarify its pathogenicity. |