ClinVar Genomic variation as it relates to human health

The R249W pathogenic variant has been previously reported as a de novo variant in multiple heterozygous patients with lamin-related congenital muscular dystrophy (L-CMD) (Quijano-Roy et al., 2008; Chemla et al., 2010). Subsequently, R249W was also been reported in individuals with a severe presentation of Emery-Dreifuss muscular dystrophy (Scharner et al., 2011; Albuquerque et al., 2014). Functional studies showed that expression of R249W in cell culture resulted in membrane defects that prevented proper cytoskeletal adaptation to mechanical stress (Bertrand et al., 2014). Additional studies indicated that R249W resulted in abnormal subcellular localization and aggregation of LMNA protein (Tan et al., 2015). The R249W 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. 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. Additionally, this substitution occurs at a position that is conserved in mammals, and missense variants in the same (R249Q) and in nearby (L248P) residues 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. Therefore, we interpret R249W as a pathogenic variant.

The LMNA c.745C>T (p.Arg249Trp) variant is a missense variant that has been reported in at least two studies, in which it is found in a de novo heterozygous state in at least four individuals with congenital muscular dystrophy (Quijano-Roy et al. 2008; Tan et al. 2015). The p.Arg249Trp variant was absent from 300 control subjects and is not found in the Genome Aggregation Database. In vitro functional studies demonstrated that the p.Arg249Trp variant affected nuclear morphology and resulted in defective mechano-responses in human myoblasts (Scharner et al. 2011; Bertrand et al. 2014; Tan et al. 2015). Based on absence from population frequency databases, identification in a de novo state, presence in affected individuals, and functional evidence, the p.Arg249Trp variant is classified as pathogenic for LMNA-related congenital muscular dystrophy.

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 249 of the LMNA protein (p.Arg249Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with infantile-onset LMNA-associated myopathy, congenital muscular dystrophy, and Emery-Dreifuss muscular dystrophy (PMID: 18551513, 20848652, 20886652, 21632249, 24508248, 24656463, 26098624, 29893365). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 14524). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects LMNA function (PMID: 20848652, 24806962, 26098624). For these reasons, this variant has been classified as Pathogenic.

PS2, PM2, PP3, PP5