ClinVar Miner

Submissions for variant NM_170707.4(LMNA):c.745C>T (p.Arg249Trp) (rs121912496)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics Inc RCV000201142 SCV000255787 pathogenic Emery-Dreifuss muscular dystrophy 2, autosomal dominant 2012-11-13 criteria provided, single submitter clinical testing
GeneDx RCV000057452 SCV000293394 pathogenic not provided 2018-12-04 criteria provided, single submitter clinical testing 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.
Laboratory of Medical Genetics, National & Kapodistrian University of Athens RCV000015621 SCV000928383 likely pathogenic Congenital muscular dystrophy, LMNA-related 2018-10-03 criteria provided, single submitter clinical testing PS2, PM2, PP3, PP5
Invitae RCV000814531 SCV000954944 pathogenic Charcot-Marie-Tooth disease, type 2 2019-04-06 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 249 of the LMNA protein (p.Arg249Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with infantile-onset LMNA-associated myopathy, congenital muscular dystrophy, and Emery-Dreifuss muscular dystrophy (EDMD), and in several of these individuals this variant was shown to arise de novo (PMID: 18551513, 20848652, 20886652, 21632249, 24508248, 26098624, 24656463, 29893365). ClinVar contains an entry for this variant (Variation ID: 14524) Experimental studies have shown that this missense change results in abnormal protein localization and nuclear shape abnormalities (PMID: 20848652, 26098624). In addition, experimental studies in cultured patient cells have shown that this missense change leads to impaired cytoskeletal adaptation in response to mechanical stress (PMID: 24806962). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000015621 SCV000035886 pathogenic Congenital muscular dystrophy, LMNA-related 2011-02-01 no assertion criteria provided literature only
Epithelial Biology; Institute of Medical Biology, Singapore RCV000057452 SCV000088566 not provided not provided no assertion provided not provided
Department of Rehabilitation Medicine, Incheon St. Mary’s Hospital,College of Medicine, The Catholic University of Korea RCV000015621 SCV000882741 pathogenic Congenital muscular dystrophy, LMNA-related 2019-02-11 no assertion criteria provided research

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