Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| New York Genome Center | RCV003228574 | SCV003925109 | likely pathogenic | Dilated cardiomyopathy 1A | 2022-04-20 | criteria provided, single submitter | clinical testing | The c.872A>T (p.Glu291Val) variant identified in the LMNA gene substitutes a well conserved Glutamic Acid for Valine at amino acid291/665 (exon 5/12). This variant is absent from population databases (gnomADv3.1.2, BRAVO-TOPMed Freeze 8, All of Us) suggesting it is not a common benign variant in the populations represented in those databases. In silico algorithms predict this variant to be Pathogenic (REVEL; score:0.9509). While the p.Glu291Val variant identified here is absent from ClinVar, a different variant at the same amino acid position, p.Glu291Lys has been reported as Pathogenic in ClinVar(VarID:200942), and reported in multiple individuals in the literature with arrhythmias, dilated cardiomyopathy, and conduction disease or heart block [PMID:25498755, 32413188]. The p.Glu291Val variant has not been previously reported in the literature in affected individuals. The p.Glu291 residue is within the Coil 2 region of the Rod domain of LMNA (UniProtKB:P02545), and other missense variants in this region have been reported in individuals with LMNA-associated cardiac phenotypes [PMID:32413188, 30402260]. Given its absence in population databases, in silico algorithms strongly predict a damaging effect to the protein, and the presence of different pathogenic missense change at the same amino acid (p.Glu291Lys), the c.872A>T (p.Glu291Val) variant identified in the LMNA gene is reported as Likely Pathogenic. |