ClinVar Genomic variation as it relates to human health

The c.250G>A (p.E84K) variant is present in dbSNP database, however, clinical significance is controversial - it was previously classified as pathogenic and as variant of unknown clinical significance. To our knowledge, the c.250G>A (p.E84K) was first described by Wilde et al. (2014). He observed three unrelated families with heterozygous carriers manifesting at their 40s with heart rhythm disturbances and progressing in DCM. We observed a family with both homozygous and heterozygous carriers; notably, 2 homozygous carriers demonstrated severe clinical features and manifested with progressive heart failure and DCM in young age. Heterozygous carriers had no complaints, but all of them were younger than 40. Family denied consanguineous marriage. Because of previously described effect of c.250G>A (p.E84K) variant in heterozygous state and severe clinical feature in homozygous carriers, we assume that this variant may demonstrate codominant features. The c.250G>A (p.E84K) variant was also absent in large population databases. Multiple lines of computational evidence predict a deleterious effect of c.250G>A (p.E84K) variant on gene or gene product. Also, LMNA gene has low rate of benign missense variants. In summary, frequency data, computational evidence and family segregation data are present, and we consider the c.250G>A (p.E84K) variant meets criteria for likely pathogenic variants.

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 84 of the LMNA protein (p.Glu84Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 23349452, 31514951). ClinVar contains an entry for this variant (Variation ID: 200953). 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 LMNA protein function. 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.

The p.E84K variant (also known as c.250G>A), located in coding exon 1 of the LMNA gene, results from a G to A substitution at nucleotide position 250. The glutamic acid at codon 84 is replaced by lysine, an amino acid with similar properties, and is located in the coil 1b domain. This alteration was reported in a patient with dilated cardiomyopathy (van Rijsingen IA et al. Eur J Heart Fail. 2013;15:376-84; van Spaendonck-Zwarts KY et al. Eur J Heart Fail. 2013;15:628-36). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear.