ClinVar Miner

Submissions for variant NM_170707.4(LMNA):c.744_745delinsTT (p.Arg249Trp)

dbSNP: rs1553265342
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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000653857 SCV000775747 pathogenic Charcot-Marie-Tooth disease type 2 2017-11-19 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 reported in individuals affected with infantile-onset LMNA-associated myopathy, congenital muscular dystrophy, and Emery-Dreifuss muscular dystrophy (EDMD) (PMID: 21632249, 20848652, 20886652, 26098624, 18551513, 24508248). In many of these individuals this variant was shown to arise de-novo (PMID: 20886652, 26098624, 18551513, 24508248). Experimental studies have shown that this missense change results in abnormal protein localization and nuclear shape abnormalities (PMID: 26098624, 20848652). 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). A different missense substitution at this codon (p.Arg249Gln) has been determined to be pathogenic (PMID: 10739764, 20980393, 21632249, 22883396, 19524666). 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.

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