Submissions for variant NM_170707.4(LMNA):c.646C>T (p.Arg216Cys)

gnomAD frequency: 0.00001  dbSNP: rs794728591

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000725540	SCV000234677	likely pathogenic	not provided	2022-08-22	criteria provided, single submitter	clinical testing	Originally reported in one individual who had either clinical or familial evidence of a laminopathy, though specific details were not provided (van Riksingen et al., 2013).; Has been reported in association with a cardiomyopathy or arrhythmia phenotype in multiple unrelated individuals referred for genetic testing at GeneDx, and in published literature (Chen et al., 2018; Armaroli et al., 2020); Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32155092, 23183350, 29943882, 30007954, 28878402, 33673806, 30078822, 34975533, 10939567)
Blueprint Genetics	RCV000208531	SCV000264008	likely pathogenic	Primary dilated cardiomyopathy	2015-03-19	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000241819	SCV000317486	pathogenic	Cardiovascular phenotype	2019-02-05	criteria provided, single submitter	clinical testing	The p.R216C pathogenic mutation (also known as c.646C>T), located in coding exon 4 of the LMNA gene, results from a C to T substitution at nucleotide position 646. The arginine at codon 216 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been identified in multiple individuals with dilated cardiomyopathy, cardiac conduction disease, and/or other laminopathy phenotypes, and it has been shown to segregate with disease in two large families (van Rijsingen IA et al. Eur J Heart Fail. 2013;15(4):376-84; Kumar S et al. Circ Arrhythm Electrophysiol. 2016;9:e004357; Nishiuchi S et al. Circ Cardiovasc Genet. 2017;10:e001603; Al-Saaidi RA et al. Eur. J. Heart Fail. 2018;ejhf.1241; Chen L et al. J Biomed Res, 2018 Jul;32:314-316; BluePrint pers. comm.; EGL pers. comm.; GeneDx pers. comm.; LMM pers. comm.; Invitae pers. comm.; Stanford pers. comm., Ambry Internal Data). In one study, neonatal rat cardiomyocytes expressing p.R216C exhibited differences in the size and distribution of lamin aggregates compared with cardiomyocytes expressing wildtype LMNA (Liu N et al. Sci Rep. 2017;7:10676). In a second study, authors showed reduced efficiency of incorporation of this alteration in the cytoskeletal fraction of patient fibroblasts (Al-Saaidi RA et al. Eur. J. Heart Fail. 2018;ejhf.1241). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Eurofins Ntd Llc (ga)	RCV000725540	SCV000337604	uncertain significance	not provided	2015-12-04	criteria provided, single submitter	clinical testing
Invitae	RCV000528116	SCV000657818	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 216 of the LMNA protein (p.Arg216Cys). This variant is present in population databases (rs794728591, gnomAD 0.01%). This missense change has been observed in individuals with conduction disease and/or dilated cardiomyopathy (PMID: 23183350, 27506821, 28878402, 29237675, 29943882, 30007954). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 200938). 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%. Experimental studies have shown that this missense change affects LMNA function (PMID: 28878402). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000182360	SCV000731751	likely pathogenic	Primary dilated cardiomyopathy; Laminopathy	2018-06-29	criteria provided, single submitter	clinical testing	The p.Arg216Cys variant in LMNA has been reported at least 10 individuals with c ardiomyopathy or other features suggestive of a laminopathy (Al-Saaidi 2018, van Rijsingen 2013, Ambry pers. comm., BluePrint pers. comm, EGL pers. comm., GeneD x pers. comm., Invitae pers. comm., Stanford pers. comm., LMM data) and segregat ed with disease in 18 affected individuals from one large family with DCM (Al-Sa aidi 2018). It has also been identified in 2/277170 chromosomes by the Genome Ag gregation Database (gnomAD, http://gnomad.broadinstitute.org) and has been repor ted in ClinVar (Variation ID:200938). Computational prediction tools and conserv ation analysis suggest that the p.Arg216Cys variant may impact the protein, thou gh this information is not predictive enough to determine pathogenicity. In summ ary, although additional studies are required to fully establish its clinical si gnificance, the p.Arg216Cys variant is likely pathogenic. ACMG/AMP Criteria appl ied: PP1_Strong, PS4_Moderate, PM2, PP3.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001778774	SCV002015100	pathogenic	Primary familial dilated cardiomyopathy	2021-10-02	criteria provided, single submitter	clinical testing	Variant summary: LMNA c.646C>T (p.Arg216Cys) results in a non-conservative amino acid change located in the Intermediate filament, rod domain (IPR039008) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251080 control chromosomes. c.646C>T has been widely reported in the literature in multiple comprehensively genotyped individuals affected with a variety of cardiac phenotypes such as, unspecified cardiac disease (van Rijsingen_2013), confirmed LMNA cardiomyopathy (Kumar_2016), RVA pacing induced HF with reduced left ventricular ejection fraction (LVEF) (Liu_2017), Atrial Firbillation and Atrioventricular block (Nishiuchi_2017), co-segregation with disease among all affected family members with DCM features of arrythmia and/or cardiomegaly (Chen_2018) and a comprehensively genotyped laboratory referral genetic testing cohort with suspected clinical diagnosis of HCM (Hathaway_2021). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in disrupted Lamin A/C nuclear location and increased apoptotic rate under environmental stress of serum starvation in a neonatal rat cardiomyocyte cell system (example, Liu_2017). Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (Pathogenic/Likely pathogenic, n=5; VUS, n=2). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as pathogenic.
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000725540	SCV000925149	uncertain significance	not provided	2017-08-17	no assertion criteria provided	provider interpretation	p.Arg216Cys (R216C; c.646C>T) in exon 4 of the LMNA gene (NM_005572.3) Given the suspicious case data and rarity in the general population, we consider this variant a variant of uncertain significance, likely pathogenic. At this time, we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). However, if the patient is able to get her family involved for segregation analysis and it segregates with disease, this variant is a good candidate for pathogenicity. The variant has been seen in at least 13 unrelated cases of cardiomyopathy (not including this patient's family). Most of these patients were seen at other genetic testing labs. Some of these patients have conduction system disease and a family history of sudden cardiac death. The case data is strong; however, segregation and functional data is lacking in any of these families, which leads us to a classification of VUS-likely pathogenic. We have seen this variant in 3 of our patients - one with cardiomyopathy, family history of sudden cardiac death/arrest, conduction system disease, arrhythmias, another with severe dilated cardiomyopathy and a family history of DCM, and another with recurrent VT and family history of VT/SVT and older-onset cardiomyopathy. This variant has been reported in one patient who is part of a multicenter cohort of 269 LMNA-positive individuals recruited in Europe with clinical or family evidence of laminopathy (van Rijsingen I et al., 2013). Ancestry is not provided. Subjects were recruited in Denmark, France, Germany, Italy, Netherlands, UK. The variant was also report in a paper on ablation for laminopathy, however the case amy be redundant with that reported by van Rijsingen et al given overlap in authors and recruitment sites and lack of details to assess potential redundancy. The variant is listed in an LMNA database online, but I can't open the variant's listing (http://www.umd.be/LMNA/W_glossary/Glossary_80C7.shtml). Ito et al (2017) included this variant in some analyses in their paper on impact of LMNA variants on splicing, however it appears it was only evaluated with an in silico algorithm and was not studied further. This is a non-conservative amino acid change, resulting in the replacement of a basic Arginine with a polar Cysteine that is capable of forming disulfide bridges. The Arginine at this location is very highly conserved across vertebrate species (it is an Asparagine in one species of bird and a Histidine in lamprey). Variants in nearby residues (F206L, I210S, L215P, L215V, K219N, K219T, H222P, H222Y, E223K, R225Q, L226V) have been reported in HGMD in association with dilated cardiomyopathy and/or muscular dystrophy, further supporting the functional importance of this region of the protein. According to the Ambry report, in silico analysis with PolyPhen predicts the variant to be “Probably Damaging” with a score of 0.97 and SIFT predicts it to be “Deleterious” with a score of (0.01). Its Grantham score is 180. According to the Invitae report, SIFT, PolyPhen-2, and Align-GVGD all suggest the variant is disruptive. The variant was reported online in 2 of 138585 individuals in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Ashkenazi, Latino descent. Specifically, the variant was observed in 1 of 10152 individuals of Ashkenazi Jewish descent (MAF=0.009850%) and 1 of 15391 South Asians (MAF=0.003249%). The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. There is one individual of “Other” ancestry with a different variant at the same codon: p.Arg216His.