ClinVar

Description

​The p.R541H suspected pathogenic variant (also known as c.1622G>A) is located in coding exon 10 of the LMNA gene. This alteration results from a G to A substitution at nucleotide position 1622. The arginine at codon 541 is replaced by histidine, an amino acid with similar properties. This variant was observed in a male proband tested in our laboratory who is affected with left ventricular noncompaction (LVNC), low ejection fraction, ventricular tachycardia, type I diabetes, history of embolic stroke and toe walking. The variant was absent in the proband's brother who is affected with LVNC. In one study, p.R541H was detected in a patient with Emery-Dreifuss muscular dystrophy who had humoperoneal myopathy, a rigid spine, and arrhythmia (Vytopil et al. 2003 J Med Genet 40:e132). In another study, p.R541H segregated with disease in a family with dilated cardiomyopathy (DCM) with conduction defects (Rudenskaya et al. 2008 Clin Genet 74:127-133). A number of alterations at the same codon have also been reported in the published literature. In one study, p.R541C was detected in a father and daughter who exhibited an atypical form of dilated cardiomyopathy with unexplained left ventricle aneurysm revealed by ventricular rhythm disturbances without atrio-ventricular block. The p.R541C mutation was apparently de novo in the father (Forissier et al. 2003 Eur J Heart Fail 5(6):821-5). In another study, the p.R541G was described in a 23-year-old patient who presented with inferolateral wall thinning and akinesis with evidence of mid-myocardial fibrosis on MRI. Notably, a marked hypertrabelculation in the dysfunctional regions was also seen on cardiac MRI (Malek et al. 2011 J Hum Genet 56:83-86). Another study detected the p.R541P mutation in a 13-year-old male who had DCM with elevated CK levels. The authors confirmed that p.R541P was a de novo mutation in this individual (van Tintelen et al. 2007 Am Heart J 154:1130-9). This variant was not reported in population-based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP) and 1000 Genomes Project. Based on protein sequence alignment in available vertebrate species, this amino acid position is highly conserved. In addition, this alteration is predicted to be possibly damaging and tolerated by PolyPhen and SIFT in silico analyses, respectively. Based on the majority of available evidence to date, this variant is likely to be pathogenic; however, its clinical significance remains unclear.