Submissions for variant NM_170707.4(LMNA):c.1130G>T (p.Arg377Leu)

dbSNP: rs61672878

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV003996497	SCV000271921	likely pathogenic	Primary dilated cardiomyopathy	2023-05-12	criteria provided, single submitter	clinical testing	The p.Arg377Leu variant in LMNA has been reported in at least 7 individuals with dilated cardiomyopathy (DCM), 3 of whom had additional features of muscular dystrophy (Ki 2002 PMID: 12032588, Boriani 2003 PMID: 12649505, van Tintelen 2007 PMID: 18035086, van Lint 2019 PMID: 30847666,Verdonschot 2020 PMID: 32880476, Stiekema 2021 PMID: 34638534, LMM data), and segregated with DCM in 2 relatives from 1 family (van Tintelen 2007 PMID: 18035086). In addition, this variant has been identified in 2 individuals with unspecified cardiomyopathy, 1 of whom also had conduction disease (te Rijdt 2017 PMID: 28759816, LMM data) as well as in at least 2 individuals with clinical features of myopathy/muscular dystrophy one of whom also had features of a conduction disorder (Madej-Pilarczyk 2018 PMID: 28987496, van Lint 2019 PMID: 30847666). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 66778) and was absent from large population studies. In vitro functional studies show abnormalities in lamin localization, supporting an impact on protein function (Stiekema 2021 PMID: 34638534, Anderson 2021 PMID: 34862408) and computational prediction tools and conservation analysis suggest that the p.Arg377Leu variant may impact the protein. Furthermore, two different substitutions at this location (p.Arg377His and p.Arg377Cys) have been reported in multiple patients with DCM and LMNA-associated muscular dystrophies (Muchir 2000 PMID: 10814726, Sebillon 2003 PMID: 12920062, Perrot 2006 PMID: 16386954, Meune 2006 PMID: 16407522, Astejada 2007 PMID: 18646565, Lashevsky 2008, Deconinck 2010 PMID: 20576434, Komaki 2011 PMID: 21632249, Sylvius 2011 PMID: 21840938, van Rijsingen 2013 PMID: 23183350, Pugh 2014 PMID: 24503780), 1 least one of which (p.Arg377His) been classified as pathogenic by multiple laboratories, suggesting that a change at this position may not be tolerated. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant DCM. ACMG/AMP Criteria applied: PM2_Supporting, PS4_Moderate, PP3, PS3_Supporting, PM5.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001237945	SCV001410737	pathogenic	Charcot-Marie-Tooth disease type 2	2024-01-22	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 377 of the LMNA protein (p.Arg377Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant LMNA-related disease (PMID: 12032588, 15678000, 18035086, 18926329, 23349452, 23360689). ClinVar contains an entry for this variant (Variation ID: 66778). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LMNA protein function with a positive predictive value of 95%. This variant disrupts the p.Arg377 amino acid residue in LMNA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10814726, 18646565, 21632249, 21840938, 23183350, 24503780). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV002321554	SCV002610638	pathogenic	Cardiovascular phenotype	2021-12-10	criteria provided, single submitter	clinical testing	The p.R377L variant (also known as c.1130G>T), located in coding exon 6 of the LMNA gene, results from a G to T substitution at nucleotide position 1130. The arginine at codon 377 is replaced by leucine, an amino acid with dissimilar properties. This alteration has been detected in subjects with dilated cardiomyopathy (DCM), as well as in subjects with varying forms of muscular dystrophy, and has been reported to segregate with disease (Ki CS et al. J. Hum. Genet., 2002;47:225-8; Boriani G et al. Stroke, 2003 Apr;34:901-8; Rudnik-Schöneborn S et al. Neurogenetics, 2007 Apr;8:137-42; Verdonschot JAJ et al. Circ Genom Precis Med, 2020 10;13:476-487). Immunofluorescence studies in patient fibroblasts demonstrated nuclear abnormalities in lamin (Stiekema M et al. Int J Mol Sci, 2021 Sep;22:[Epub ahead of print]). In addition, other alterations affecting the same amino acid, p.R377C (c.1129C>T) and p.R377H (c.1130G>A), have been reported in individuals with DCM and other laminopathies, and the p.R377H variant has shown significant co-segregation in affected relatives from multiple families (Muchir A et al. Hum. Mol. Genet., 2000 May;9:1453-9; Charniot JC et al. Hum. Mutat., 2003 May;21:473-81; Sébillon P et al. J. Med. Genet., 2003 Aug;40:560-7; Perrot A et al. Eur. J. Heart Fail., 2006 Aug;8:484-93; Astejada MN et al. Acta Myol, 2007 Dec;26:159-64). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Neuberg Centre For Genomic Medicine, NCGM	RCV003448256	SCV004176574	pathogenic	Congenital muscular dystrophy due to LMNA mutation	2023-02-14	criteria provided, single submitter	clinical testing	The missense c.1130G>T (p.Arg377Leu) variant in LMNA gene has been reported previously in heterozygous state in multiple individuals affected with LMNA-related muscular dystrophy (van Tintelen et al. 2007; Chen et al. 2013; Madej-Pilarczyk et al. 2018). The p.Arg377Leu variant is novel (not in any individuals) in both gnomAD Exomes and 1000 Genomes databases. This variant has been reported to the ClinVar database as Uncertain Significance / Pathogenic (multiple submissions). The amino acid change p.Arg377Leu in LMNA is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Arg at position 377 is changed to a Leu changing protein sequence and it might alter its composition and physico-chemical properties. Another missense variant [p.Arg377Cys] at this residue has previously been reported to affect protein function or expression (Sylvius et al. 2011). For these reasons, this variant has been classified as Pathogenic.
All of Us Research Program, National Institutes of Health	RCV003996497	SCV004825165	likely pathogenic	Primary dilated cardiomyopathy	2023-08-15	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with leucine at codon 377 of the intermediate filament rod domain of the lamin A/C protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in multiple individuals affected with dilated cardiomyopathy (PMID: 12649505, 18035086, 18926329, 23349452, 32880476). This variant has also been reported in individuals affected with a range of laminopathy phenotypes, including atrial fibrillation (PMID: 35449878), Emery-Dreifuss muscular dystrophy (PMID: 12649505), limb-girdle muscular dystrophy (PMID: 15832002), and muscle weakness (PMID: 32528171). Different variants affecting the same codon, p.Arg377Cys and p.Arg377His, are considered to be disease-causing for dilated cardiomyopathy (Clinvar variation ID: 14495 and 48031), indicating that arginine at this position is important for LMNA protein function. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Epithelial Biology; Institute of Medical Biology, Singapore	RCV000057236	SCV000088349	not provided	not provided		no assertion provided	not provided
Clinical Genetics, Academic Medical Center	RCV000057236	SCV001918438	pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000057236	SCV001930510	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000057236	SCV001955774	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000057236	SCV001965087	pathogenic	not provided		no assertion criteria provided	clinical testing