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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