Total submissions: 6
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Genetic Services Laboratory, |
RCV000503996 | SCV000595627 | pathogenic | Muscular dystrophy | 2013-02-08 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV000547164 | SCV000657791 | pathogenic | Charcot-Marie-Tooth disease, type 2 | 2019-10-16 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine with histidine at codon 377 of the LMNA protein (p.Arg377His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to segregate with limb girdle muscular dystrophy with atrioventricular conduction disturbances (LGMD1B) in one family (PMID: 10814726) and with dilated cardiomyopathy with a quadricep-specific skeletal myopathy in a second family (PMID: 12673789). This variant has also been reported in several unrelated individuals affected with LGMD1B (PMID: 24990833, 27220833, 26443318). ClinVar contains an entry for this variant (Variation ID: 14495). Experimental studies have shown that this missense change impacts LMNA protein function, leading to laminin A mislocalization within the cell and decreased laminin A/emerin interaction (PMID: 12673789, 19524666). A different missense substitution at this codon (p.Arg377Cys) has been determined to be pathogenic (PMID: 21840938, 18646565, 24503780, 23183350, 21632249). This suggests that the arginine residue is critical for LMNA protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic. |
| EGL Genetic Diagnostics, |
RCV000057235 | SCV000707955 | pathogenic | not provided | 2018-05-07 | criteria provided, single submitter | clinical testing | |
| Agnes Ginges Centre for Molecular Cardiology, |
RCV001089610 | SCV001245084 | pathogenic | Sudden unexplained death | 2018-08-21 | criteria provided, single submitter | research | LMNA Arg377His has been reported in multiple probands and families who have one or more of the associated phenotypes in the 'laminopathy' disease spectrum which includes neuromuscular, cardiac, metabolic disorders and premature aging syndromes (Schneiders et al., 2017; Furuta et al., 2016; Madej-Pilarczyk et al., 2015; Sakiyama et al., 2014; Sylvius et al., 2011; Emerson et al., 2009; Rudenskaya et al., 2008; Benedetti et al., 2007; Rudnik-Schoneborn et al., 2007; van Tintelen et al., 2007; Perrot et al., 2006; Sebillon et al., 2003; Taylor et al., 2003; Muchir et al., 2000) and was found to segregate in multiple affected individuals within several families (Rudnik-Schoneborn et al., 2007; van Tintelen et al., 2007; Perrot et al., 2006; Charniot et al., 2003; Taylor et al., 2003; Muchir et al., 2000). We identified this variant in a proband who died suddenly without any cause on postmortem. The variant is also extremely rare as it absent from the Genome Aggregation Database (http://gnomad.broadinstitute.org/). In silico tools SIFT, PolyPhen2 and MutationTaster all predict this variant to be deleterious. Furthermore multiple functional studies suggest that this variant affects both lamin and emerin protein localisation (Emerson et al., 2009; Reichart et al., 2004; Sebillon et al., 2003; Charniot et al., 2003). In summary, this variant has been reported in many probands within the laminopathy spectrum, has been found to segregate strongly within families, functional studies confirm that the variant disrupts protein function, the variant is also rare, in silico tools predict it to be deleterious and missense variants in LMNA are not only rare but are a known mechanism of disease, therefore we classify LMNA Arg377His as 'pathogenic'. |
| OMIM | RCV000681569 | SCV000035851 | pathogenic | Emery-Dreifuss muscular dystrophy 2, autosomal dominant | 2007-04-01 | no assertion criteria provided | literature only | |
| Epithelial Biology; Institute of Medical Biology, |
RCV000057235 | SCV000088348 | not provided | not provided | no assertion provided | not provided |