rs794728591
Variant summary
Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1PP3_ModeratePP5
The NM_170707.4(LMNA):c.646C>T(p.Arg216Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,614,056 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/23 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R216H) has been classified as Uncertain significance.
Frequency
Consequence
NM_170707.4 missense
Scores
Clinical Significance
Conservation
Publications
- dilated cardiomyopathyInheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
- dilated cardiomyopathy 1AInheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Ambry Genetics, Orphanet
- familial partial lipodystrophy, Dunnigan typeInheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae)
- Hutchinson-Gilford progeria syndromeInheritance: AD, SD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
- restrictive dermopathy 2Inheritance: AR, AD Classification: DEFINITIVE, LIMITED Submitted by: G2P
- Emery-Dreifuss muscular dystrophy 2, autosomal dominantInheritance: SD, AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
- atrioventricular blockInheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
- heart-hand syndrome, Slovenian typeInheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, G2P
- Charcot-Marie-Tooth disease type 2B1Inheritance: AR, AD Classification: STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: G2P, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
- Emery-Dreifuss muscular dystrophy 3, autosomal recessiveInheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
- mandibuloacral dysplasia with type A lipodystrophyInheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
- atrial fibrillationInheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
- atypical Werner syndromeInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- autosomal dominant Emery-Dreifuss muscular dystrophyInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- congenital muscular dystrophy due to LMNA mutationInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- familial isolated dilated cardiomyopathyInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- lethal restrictive dermopathyInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- LMNA-related cardiocutaneous progeria syndromeInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- autosomal recessive Emery-Dreifuss muscular dystrophyInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
- dilated cardiomyopathy-hypergonadotropic hypogonadism syndromeInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
- autosomal semi-dominant severe lipodystrophic laminopathyInheritance: SD Classification: SUPPORTIVE Submitted by: Orphanet
- arrhythmogenic right ventricular cardiomyopathyInheritance: AD Classification: LIMITED Submitted by: ClinGen
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ACMG classification
Our verdict: Uncertain_significance. The variant received 5 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| LMNA | NM_170707.4 | c.646C>T | p.Arg216Cys | missense_variant | Exon 4 of 12 | ENST00000368300.9 | NP_733821.1 | |
| LMNA | NM_005572.4 | c.646C>T | p.Arg216Cys | missense_variant | Exon 4 of 10 | ENST00000677389.1 | NP_005563.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| LMNA | ENST00000368300.9 | c.646C>T | p.Arg216Cys | missense_variant | Exon 4 of 12 | 1 | NM_170707.4 | ENSP00000357283.4 | ||
| LMNA | ENST00000677389.1 | c.646C>T | p.Arg216Cys | missense_variant | Exon 4 of 10 | NM_005572.4 | ENSP00000503633.1 |
Frequencies
GnomAD3 genomes 0.00000657 AC: 1AN: 152174Hom.: 0 Cov.: 32 show subpopulations
GnomAD2 exomes AF: 0.00000398 AC: 1AN: 251080 AF XY: 0.00000736 show subpopulations
GnomAD4 exome AF: 0.00000547 AC: 8AN: 1461882Hom.: 0 Cov.: 33 AF XY: 0.00000413 AC XY: 3AN XY: 727240 show subpopulations
Age Distribution
GnomAD4 genome 0.00000657 AC: 1AN: 152174Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74326 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
not provided Pathogenic:3Uncertain:2
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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 (PMID: 30007954, 32155092); Originally reported in one individual who had either clinical or familial evidence of a laminopathy, though specific details were not provided (PMID: 23183350); Not observed at 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, 33673806, 30078822, 34975533, 10939567, 38048861, 38979608, 28878402, 34495297, 36704457, 29237675, 27506821, 23183350, 30007954, 29943882, 36243179, 36548481, 38756545) -
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. -
The frequency of this variant in the general population is consistent with pathogenicity. (http://gnomad.broadinstitute.org) This variant associates in multiple families with autosomal dominant cardiac conduction disease and/or dilated cardiomyopathy. Assessment of experimental evidence suggests this variant results in abnormal protein function. Studies showed impaired localization of Lamin A/C in the nuclear envelope (PMID:28878402, 29943882). -
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Primary dilated cardiomyopathy Pathogenic:2
The c.646C>T (p.Arg216Cys) variant of the LMNA gene replaces arginine with cysteine at codon 216. This change has been reported in multiple individuals with dilated cardiomyopathy (PMID 23183350, 27506821, 29237675, 29943882, 30007954, 34975533) and conduction disease (PMID: 32155092). This variant has been reported to segregate with disease in 19 affected individuals in one large family, however this variant was also observed 9 asymptomatic carriers in the same family, suggesting incomplete penetrance (PMID: 29943882). Experimental analysis of this variant in rat cardiomyocytes and patient specific human induced pluripotent stem cells demonstrated increased cellular apoptosis, irregular nuclear shape, increased percentage of laminal structure impairment (PMID: 28878402, 34975533). Computational evidence suggests this variant is detrimental to LMNA protein function (REVEL score 0.833). The frequency of this variant in the general population database (gnomAD) is rare (0.001%). Another variant disrupting the same variant has been interpreted as pathogenic (Clinvar Variation ID: 200938). Clinvar contains an entry for this variant (variation ID 200938). Based on the available evidence, the c.646C>T (p.Arg216Cys) variant of the LMNA gene is classified as likely pathogenic. -
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Cardiovascular phenotype Pathogenic:2
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. -
PP1_strong, PS3_mod, PS4_mod, PM2, PM5_supp, PP2, PP3, PP5 -
Charcot-Marie-Tooth disease type 2 Pathogenic:1
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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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. -
Primary dilated cardiomyopathy;C5392094:Laminopathy Pathogenic:1
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. -
Primary familial dilated cardiomyopathy Pathogenic:1
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. -
Atrioventricular block Pathogenic:1
Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0103 - Both loss and gain of function are known mechanisms of disease for this gene (PMID: 17377071). (N) 0104 - Dominant negative is a mechanism of disease for this gene (PMID: 17377071). (N) 0108 - This gene is known to be associated with both recessive and dominant disease (OMIM) (N) 0112 - Variants in this gene are known to have reduced penetrance (OMIM, GeneReviews). (N) 0200 - Variant is predicted to result in a missense amino acid change from arginine to cysteine (exon 4). (N) 0251 - Variant is heterozygous. (N) 0302 - Variant is present in gnomAD <0.001 for a dominant condition (2 heterozygotes, 0 homozygotes). (P) 0309 - Alternative amino acid changes at the same position have been observed in gnomAD: p.(Arg216His) at 0.002% (7 heterozygotes, 0 homozygotes), and p.(Arg216Leu) at 0.003% (1 heterozygote, 0 homozygotes). (N) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (P) 0600 - Variant is located in an annotated domain or motif. The variant is located in the Coil 1B domain (PDB). (N) 0708 - Comparable variants have conflicting previous evidence for pathogenicity. p.(Arg216His) has four VUS entries in ClinVar. p.(Arg216His) has also been identified in a DCM patient with nuclear abnormalities consistent with a laminopathy (PMID: 30420677). (N) 0802 - Moderate previous evidence of pathogenicity in unrelated individuals. This variant has been reported in multiple patients with DCM and arrhythmias however, it has demonstrated reduced penetrance (PMID: 29943882; PMID: 30007954; PMID: 29237675; PMID: 23183350). This variant has two pathogenic, three likely pathogenic, and two VUS entries in ClinVar. (P) 0903 - Low evidence for segregation with disease. The variant has segregated with atrioventricular block and DCM in 25 individuals in two families. The variant was also identified in 14 unaffected carriers in these families (PMID: 29943882; PMID 30007954). (P) 1002 - Moderate functional evidence supporting abnormal protein function. Neonatal rat cardiomyocytes transfected with this variant had irregular nucleus and the localization of Lamin A/C proteins appeared profoundly impaired compared to wild-type (PMID: 28878402). (P) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at