Submissions for variant NM_170707.4(LMNA):c.1201C>T (p.Arg401Cys) (rs61094188)

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section,National Institutes of Health	RCV000172002	SCV000054719	uncertain significance	Emery-Dreifuss muscular dystrophy	2013-06-24	criteria provided, single submitter	research
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine	RCV000041313	SCV000065005	uncertain significance	not specified	2017-05-23	criteria provided, single submitter	clinical testing	The p.Arg401Cys variant in LMNA has been reported in 1 individual with Emery Dre ifuss muscular dystrophy who carried a second LMNA variant (p.Thr150fs), which w as also present in the father who suffered sudden cardiac death. The p.Arg401Cys variant was also identified in the reportedly unaffected mother and sister (Han isch 2002, Vytopil 2002, Muchir 2004, Emerson 2009). This variant was also ident ified in 2 individuals with DCM (one with neonatal onset), segregated with disea se in 1 affected relative (Chami 2014, LMM data) and has also been reported in C linVar (Variation ID 48035). It has been identified in 6/34400 of Latino chromos omes and 11/126264 of European chromosomes by the Genome Aggregation Consortium (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs61094188). Computational pred iction tools and conservation analysis do not provide strong support for or agai nst an impact to the protein. In summary, the clinical significance of the p.Arg 401Cys variant is uncertain.
GeneDx	RCV000057258	SCV000234697	uncertain significance	not provided	2018-12-20	criteria provided, single submitter	clinical testing	The R401C variant in the LMNA gene has been reported as a heterozygous variant in an individual with Emery-Dreifuss muscular dystrophy (EDMD), as well as in the individual's unaffected mother and sister (Vytopil et al., 2002). R401C was also observed in trans with another LMNA variant (c.447insC) in a different individual with EDMD and was found to be inherited from a parent without neuromuscular disease (Emerson, et al., 2009). Additionally, the R401C variant was observed in two siblings with dilated cardiomyopathy who may or may not have had additional variants in other cardiomyopathy-related genes (Chami et al., 2014). Nevertheless, this variant is observed in 2 /11,536 alleles (0.02%) from individuals of Latino ancestry in large population cohorts (Lek et al., 2016) and in multiple unaffected individuals referred for genetic testing at GeneDx. The R401C 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. This substitution alters a highly conserved position within the Tail region of the LMNA protein. Furthermore, in silico analysis predicts this variant is probably damaging to the protein structure/function.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics	RCV000057258	SCV000337619	uncertain significance	not provided	2018-05-17	criteria provided, single submitter	clinical testing
Invitae	RCV000528639	SCV000657795	uncertain significance	Charcot-Marie-Tooth disease, type 2	2019-11-01	criteria provided, single submitter	clinical testing	This sequence change replaces arginine with cysteine at codon 401 of the LMNA protein (p.Arg401Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs61094188, ExAC 0.02%). This variant has been reported in an individual affected with muscular dystrophy (PMID: 12376891), as well as several related individuals with dilated cardiomyopathy (PMID: 25448463). However, in the individual with muscular dystrophy, this variant was also observed in their unaffected sister and mother so the clinical significance of this observation is uncertain. ClinVar contains an entry for this variant (Variation ID: 48035). Experimental studies have shown that this missense has varying effects on the binding of known lamin-A interacting proteins (PMID: 14597414, 23977161, 24623722, 28531892). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute	RCV000627127	SCV000747935	likely pathogenic	Dilated cardiomyopathy 1B	2017-02-17	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario	RCV000769728	SCV000901149	uncertain significance	Cardiomyopathy	2015-09-30	criteria provided, single submitter	clinical testing
Blueprint Genetics	RCV000057258	SCV000927502	uncertain significance	not provided	2017-12-28	criteria provided, single submitter	clinical testing
Molecular Genetics Laboratory,London Health Sciences Centre	RCV001172616	SCV001335679	uncertain significance	Charcot-Marie-Tooth disease		criteria provided, single submitter	clinical testing
Color	RCV000769728	SCV001355731	uncertain significance	Cardiomyopathy	2020-01-01	criteria provided, single submitter	clinical testing
Epithelial Biology; Institute of Medical Biology, Singapore	RCV000057258	SCV000088371	not provided	not provided		no assertion provided	not provided
Blueprint Genetics	RCV000157295	SCV000207027	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia type 1	2014-08-19	no assertion criteria provided	clinical testing