ClinVar Miner

Submissions for variant NM_170707.4(LMNA):c.1129C>T (p.Arg377Cys) (rs397517889)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Center of Genomic medicine, Geneva,University Hospital of Geneva RCV000592134 SCV000897957 pathogenic Dilated cardiomyopathy 1A 2018-08-01 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000223811 SCV000704169 likely pathogenic not provided 2016-12-16 criteria provided, single submitter clinical testing
GeneDx RCV000223811 SCV000292600 pathogenic not provided 2018-08-30 criteria provided, single submitter clinical testing The R377C pathogenic variant in the LMNA gene has been reported in multiple unrelated individuals with cardiomyopathy or laminopathy (Astejada et al., 2007; Mejat et al., 2009; Deconinck et al., 2010; Komaki et al., 2011; Sylvius et al., 2011; Narula et al., 2012; van Rijsingen et al., 2013; Pugh et al., 2014; Kumar et al., 2016; Walsh et al., 2017). This variant has also been classified in ClinVar as pathogenic/likely pathogenic by other clinical laboratories (ClinVar SCV000548870.1, SCV000065000.4; Landrum et al., 2016). The R377C variant is also not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R377C 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 occurs within the alpha-helical rod domain of the LMNA gene, at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Finally, pathogenic/likely pathogenic variants in the same residue (R377L, R377H) have also been reported in the Human Gene Mutation Database in association with LMNA-related disorders (Stenson et al., 2014), supporting the functional importance of this residue.
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.
Invitae RCV000469099 SCV000548870 pathogenic Charcot-Marie-Tooth disease, type 2 2018-11-29 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 377 of the LMNA protein (p.Arg377Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals and families affected with cardiomyopathy and muscular dystrophy (PMID: 21840938, 18646565, 24503780, 23183350, 21632249). ClinVar contains an entry for this variant (Variation ID: 48031). A different missense substitution at this codon (p.Arg377His) has been determined to be pathogenic (PMID: 12628721, 16386954, 15053843, 12673789). 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.
Laboratory for Molecular Medicine,Partners HealthCare 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
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).

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