ClinVar Miner

Submissions for variant NM_170707.4(LMNA):c.122G>T (p.Arg41Leu) (rs1060502215)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics Inc RCV000518408 SCV000614024 uncertain significance not specified 2017-06-08 criteria provided, single submitter clinical testing
Invitae RCV000653844 SCV000775734 likely pathogenic Charcot-Marie-Tooth disease, type 2 2017-08-17 criteria provided, single submitter clinical testing This sequence change replaces arginine with leucine at codon 41 of the LMNA protein (p.Arg41Leu). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and leucine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to be de novo in an individual affected with Emery-Dreifuss muscular dystrophy (Achmad 2017  http://www.jafib.com/PMC/XML/Inprogress/1511/1511pdf_almira_zada.pdf ). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. A different missense substitution at this codon (p.Arg41His) has been determined to be pathogenic (Invitae database).  Additional amino acid substitutions at this codon (p.Arg41Ser and p.Arg41Cys) have also been reported in an individual affected with infantile inflammatory myopathy and an individual affected with LMNA-related congenital muscular dystrophy (PMID: 20980393). This suggests that the arginine residue is critical for LMNA protein function and that other missense substitutions at this position may also be pathogenic. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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