rs794728591
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2PM5PP2PP3_ModeratePP5_Very_Strong
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. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R216H) has been classified as Likely pathogenic.
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000055 ( 0 hom. )
Consequence
LMNA
NM_170707.4 missense
NM_170707.4 missense
Scores
16
3
1
Clinical Significance
Conservation
PhyloP100: 2.65
Genes affected
LMNA (HGNC:6636): (lamin A/C) The protein encoded by this gene is part of the nuclear lamina, a two-dimensional matrix of proteins located next to the inner nuclear membrane. The lamin family of proteins make up the matrix and are highly conserved in evolution. During mitosis, the lamina matrix is reversibly disassembled as the lamin proteins are phosphorylated. Lamin proteins are thought to be involved in nuclear stability, chromatin structure and gene expression. Vertebrate lamins consist of two types, A and B. Alternative splicing results in multiple transcript variants. Mutations in this gene lead to several diseases: Emery-Dreifuss muscular dystrophy, familial partial lipodystrophy, limb girdle muscular dystrophy, dilated cardiomyopathy, Charcot-Marie-Tooth disease, and Hutchinson-Gilford progeria syndrome. [provided by RefSeq, May 2022]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 17 ACMG points.
PM1
In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 12 uncertain in NM_170707.4
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr1-156134812-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 200964.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=9, Likely_pathogenic=2}.
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), LMNA. . Gene score misZ 2.3673 (greater than the threshold 3.09). Trascript score misZ 3.0905 (greater than threshold 3.09). GenCC has associacion of gene with familial partial lipodystrophy, Dunnigan type, autosomal recessive Emery-Dreifuss muscular dystrophy, LMNA-related cardiocutaneous progeria syndrome, atrioventricular block, dilated cardiomyopathy 1A, Emery-Dreifuss muscular dystrophy 2, autosomal dominant, atypical Werner syndrome, restrictive dermopathy 1, autosomal semi-dominant severe lipodystrophic laminopathy, Emery-Dreifuss muscular dystrophy 3, autosomal recessive, dilated cardiomyopathy, Charcot-Marie-Tooth disease type 2B1, dilated cardiomyopathy-hypergonadotropic hypogonadism syndrome, arrhythmogenic right ventricular cardiomyopathy, familial isolated dilated cardiomyopathy, mandibuloacral dysplasia with type A lipodystrophy, autosomal dominant Emery-Dreifuss muscular dystrophy, heart-hand syndrome, Slovenian type, congenital muscular dystrophy due to LMNA mutation, lethal restrictive dermopathy, Hutchinson-Gilford progeria syndrome.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.894
PP5
Variant 1-156134811-C-T is Pathogenic according to our data. Variant chr1-156134811-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 200938.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| LMNA | NM_170707.4 | c.646C>T | p.Arg216Cys | missense_variant | 4/12 | ENST00000368300.9 | NP_733821.1 | |
| LMNA | NM_005572.4 | c.646C>T | p.Arg216Cys | missense_variant | 4/10 | ENST00000677389.1 | NP_005563.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| LMNA | ENST00000368300.9 | c.646C>T | p.Arg216Cys | missense_variant | 4/12 | 1 | NM_170707.4 | ENSP00000357283.4 | ||
| LMNA | ENST00000677389.1 | c.646C>T | p.Arg216Cys | missense_variant | 4/10 | NM_005572.4 | ENSP00000503633.1 |
Frequencies
GnomAD3 genomes 0.00000657 AC: 1AN: 152174Hom.: 0 Cov.: 32
GnomAD3 genomes
AF:
AC:
1
AN:
152174
Hom.:
Cov.:
32
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251080Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135872
GnomAD3 exomes
AF:
AC:
1
AN:
251080
Hom.:
AF XY:
AC XY:
1
AN XY:
135872
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.00000547 AC: 8AN: 1461882Hom.: 0 Cov.: 33 AF XY: 0.00000413 AC XY: 3AN XY: 727240
GnomAD4 exome
AF:
AC:
8
AN:
1461882
Hom.:
Cov.:
33
AF XY:
AC XY:
3
AN XY:
727240
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome 0.00000657 AC: 1AN: 152174Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74326
GnomAD4 genome
AF:
AC:
1
AN:
152174
Hom.:
Cov.:
32
AF XY:
AC XY:
1
AN XY:
74326
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Alfa
AF:
Hom.:
Bravo
AF:
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:9Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:2Uncertain:2
| Uncertain significance, flagged submission | provider interpretation | Stanford Center for Inherited Cardiovascular Disease, Stanford University | Aug 17, 2017 | 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. - |
| Uncertain significance, flagged submission | clinical testing | Eurofins Ntd Llc (ga) | Dec 04, 2015 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 31, 2024 | 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, 36243179, 36548481, 34975533, 10939567, 38756545, 38048861, 38979608, 28878402, 34495297, 36704457, 29237675, 27506821, 23183350, 29943882, 30007954) - |
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics Laboratory, Skane University Hospital Lund | Oct 31, 2023 | - - |
Primary dilated cardiomyopathy Pathogenic:2
| Likely pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Sep 28, 2024 | 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. - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Blueprint Genetics | Mar 19, 2015 | - - |
Charcot-Marie-Tooth disease type 2 Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 15, 2024 | 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. - |
Primary familial dilated cardiomyopathy Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 02, 2021 | 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. - |
Primary dilated cardiomyopathy;C5392094:Laminopathy Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jun 29, 2018 | 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. - |
Cardiovascular phenotype Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 05, 2019 | 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. - |
Atrioventricular block Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Jun 11, 2020 | 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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
CardioboostCm
Uncertain
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Pathogenic
.;.;.;D;.;.;.;D;.
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Pathogenic
D;D;D;D;D;D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
M;.;M;M;M;.;.;.;.
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D;D;D;D;D;D;D;D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D;D;D;D;D;D;D;D
Sift4G
Pathogenic
D;D;D;D;D;D;D;D;D
Polyphen
D;.;D;D;.;.;D;.;.
Vest4
MutPred
Loss of MoRF binding (P = 0.0067);Loss of MoRF binding (P = 0.0067);Loss of MoRF binding (P = 0.0067);Loss of MoRF binding (P = 0.0067);Loss of MoRF binding (P = 0.0067);.;.;.;.;
MVP
MPC
2.4
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at