Submissions for variant NM_170707.4(LMNA):c.1129C>T (p.Arg377Cys)

gnomAD frequency: 0.00001  dbSNP: rs397517889

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000041308	SCV000065000	likely pathogenic	Primary dilated cardiomyopathy	2016-11-09	criteria provided, single submitter	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory
GeneDx	RCV000223811	SCV000292600	pathogenic	not provided	2021-03-03	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 15678000, 21840938, 20474083, 18035086, 10814726, 12920062, 21632249, 16407522, 19124654, 18646565, 20576434, 24503780, 23183350, 26060040, 27532257, 23062543, 27506821, 12032588, 16386954, 21483645, 31410651, 31296281, 31447099)
Invitae	RCV000469099	SCV000548870	pathogenic	Charcot-Marie-Tooth disease type 2	2024-01-15	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 377 of the LMNA protein (p.Arg377Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with cardiomyopathy and muscular dystrophy (PMID: 18646565, 21632249, 21840938, 23183350, 24503780). ClinVar contains an entry for this variant (Variation ID: 48031). 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: 12628721, 12673789, 15053843, 16386954). 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.
Eurofins Ntd Llc (ga)	RCV000223811	SCV000704169	likely pathogenic	not provided	2016-12-16	criteria provided, single submitter	clinical testing
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000592134	SCV000840004	likely pathogenic	Dilated cardiomyopathy 1A	2017-05-25	criteria provided, single submitter	clinical testing	This c.1129C>T (p.Arg377Cys) variant in the LMNA gene has previously been reported in a 49 year old male with a diagnosis and a family history of DCM [PMID 24503780] and was also detected in a 10 y/o female who died of heart failure, with unsteady gait, diagnosed at the age of 7 with DCM [PMID 21632249]. This variant was also detected in a cohort of patients with muscular dystrophy [PMID 18646565] and a cohort of patients with cardiac disease [PMID 23183350]. Additional variants affecting the same amino acid at position 377 (p.Arg377His and p.Arg377Leu) have been reported in patients with cardiomyopathy and muscular dystrophy. Arginine at position 377 of the LMNA protein is highly conserved in mammals and has not been observed in the ExAC database. While not validated for clinical use, the computer-based algorithms SIFT and Polyphen-2 predict this Arg377Cys change to be deleterious. It is thus interpreted as a likely pathogenic variant.
Center of Genomic medicine, Geneva, University Hospital of Geneva	RCV000592134	SCV000897957	pathogenic	Dilated cardiomyopathy 1A	2018-08-01	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000223811	SCV002022699	likely pathogenic	not provided	2020-11-16	criteria provided, single submitter	clinical testing
Eurofins-Biomnis	RCV003236576	SCV003935030	pathogenic	Charcot-Marie-Tooth disease type 2B1	2022-09-23	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003343619	SCV004074605	pathogenic	Cardiovascular phenotype	2023-06-29	criteria provided, single submitter	clinical testing	The p.R377C pathogenic mutation (also known as c.1129C>T), located in coding exon 6 of the LMNA gene, results from a C to T substitution at nucleotide position 1129. The arginine at codon 377 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been reported in multiple individuals with laminopathies, including dilated cardiomyopathy (DCM), Emery-Dreifuss muscular dystrophy, and limb girdle muscular dystrophy (Deconinck N et al. Neuromuscul Disord, 2010 Aug;20:517-23; Komaki H et al. Neuromuscul Disord, 2011 Aug;21:563-8; Sylvius N et al. FASEB J, 2011 Nov;25:3966-78; Pugh TJ et al. Genet Med, 2014 Aug;16:601-8; Hasselberg NE et al. Eur Heart J, 2018 Mar;39:853-860; Cotta A et al. J Mol Neurosci, 2019 Dec;69:623-627; Krenn M et al. Eur J Neurol, 2022 Jun;29:1815-1824; Pessente GD et al. Front Cardiovasc Med, 2022 Apr;9:823717). Two other alterations at the same codon, p.R377L (c.1130G>T) and p.R377H (c.1130G>A), have been detected in subjects with DCM, as well as in subjects with varying forms of muscular dystrophy, and have been reported to segregate with disease (Muchir A et al. Hum. Mol. Genet., 2000 May;9:1453-9; Ki CS et al. J. Hum. Genet., 2002;47:225-8; Boriani G et al. Stroke, 2003 Apr;34:901-8; Charniot JC et al. Hum. Mutat., 2003 May;21:473-81; Sébillon P et al. J. Med. Genet., 2003 Aug;40:560-7; Rudnik-Schöneborn S et al. Neurogenetics, 2007 Apr;8:137-42; Verdonschot JAJ et al. Circ Genom Precis Med, 2020 10;13:476-487). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This alteration is predicted to be deleterious by BayesDel in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000223811	SCV000280179	likely pathogenic	not provided	2015-03-18	no assertion criteria provided	clinical testing	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. LMNA p.Arg377Cys Given the case data and lack of presence in general population databases (reviewed below) we consider this variant as likely disease causing. The variant has been seen in at least five unrelated cases with cardiomyopathy or laminopathy in the literature. There is segregation data on family members in the reported cases. Astejada M. et al., 2008 reported c.1129 C>T in one Japanese individual with muscular dystrophy with nuclear envelopathy. No specific details were provided. Komaki H et al., 2011 reported R377C in one female who died at 7 yo from heart failure. She had an unsteady gate and a CK of 1000 at biopsy. Cardiac involvement included DCM diagnosed at 7 yo with an EF of 32%. She had joint contractures of her ankles and no respiratory dysfunction. Sylvius et al., 2011 reported c.1129C>T in two unrelated individuals. One was diagnosed at 42 yo after having difficulty climbing stairs. (S)he had pelvic and muscle weakness, axial muscle wasting, no contractures cardiomyopathy with CD and ICD and was last examined at age 56. The other patient was diagnosed at age 40 after having difficulty climbing stairs. (S)he also had pelvic muscle weakness with cardiac conduction defects and arrhythmia and their last reported evaluation before publication was at age 67. Van Rijsingen et al., 2013 reported this variant in one individual with this variant in their large cohort of LMNA mutation carriers but no individual data was provided. Similar changes at the same amino acid are summarized below: Charniot et al., 2003 reported a family harboring the R377H variant. 12 family members are positive for the R377H variant in lamin A. Of those, 11/12 have a DCM phenotype. The one unaffected individual is the youngest of the mutation positive family members at 21 yo. 4/10 evaluated mutation positive family members have a muscular phenotype, and 1/10 additional family members has a borderline study at age 33 yo. All of the individuals in their 30s and 40s had a reduced ejection fraction (<55%), while those in their 20s had ejection fractions in the 60s. Complete left bundle branch block was found in 5/8 evaluated individuals 4/8 also had some level of AV block (including two individuals who had both LBBB and AVB. 9/12 individuals had some level of AF and 4 had episodes of VT. Every mutation positive family member over the age of 21 had some form of conduction system disease. Muchir et al., 2000 reported a carribean family with the R377H variant. Eight individuals were evaluated. This family reported musculoskeletal, cardiomyopathy and AV conduction system defects. In silico analysis with PolyPhen-2 predicts the variant to be damaging. The argenine at codon is conserved across species, as are neighboring amino acids. Other variants have been reported in association with disease at this codon 377 and nearby codons. In total the variant has not been seen in individuals from publicly available population datasets. There is no variation at codon 377 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on Caucasian and African American individuals (as of October 29, 2014).