ClinVar Miner

Submissions for variant NM_170707.4(LMNA):c.1130G>A (p.Arg377His) (rs61672878)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory, University of Chicago RCV000503996 SCV000595627 pathogenic Muscular dystrophy 2013-02-08 criteria provided, single submitter clinical testing
Invitae RCV000547164 SCV000657791 pathogenic Charcot-Marie-Tooth disease, type 2 2018-06-27 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,Eurofins Clinical Diagnostics RCV000057235 SCV000707955 pathogenic not provided 2018-05-07 criteria provided, single submitter clinical testing
OMIM RCV000681569 SCV000035851 pathogenic Benign scapuloperoneal muscular dystrophy with cardiomyopathy 2007-04-01 no assertion criteria provided literature only
Epithelial Biology; Institute of Medical Biology, Singapore RCV000057235 SCV000088348 not provided not provided no assertion provided not provided

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