1-156136257-C-T
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Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP2PP3
The NM_170707.4(LMNA):c.1201C>T(p.Arg401Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000732 in 1,611,838 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R401H) has been classified as Uncertain significance.
Frequency
Genomes: 𝑓 0.00013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000067 ( 0 hom. )
Consequence
LMNA
NM_170707.4 missense
NM_170707.4 missense
Scores
7
11
2
Clinical Significance
Conservation
PhyloP100: 3.64
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]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 4 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
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, 0.798
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| LMNA | NM_170707.4 | c.1201C>T | p.Arg401Cys | missense_variant | 7/12 | ENST00000368300.9 | NP_733821.1 | |
| LMNA | NM_005572.4 | c.1201C>T | p.Arg401Cys | missense_variant | 7/10 | ENST00000677389.1 | NP_005563.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| LMNA | ENST00000368300.9 | c.1201C>T | p.Arg401Cys | missense_variant | 7/12 | 1 | NM_170707.4 | ENSP00000357283.4 | ||
| LMNA | ENST00000677389.1 | c.1201C>T | p.Arg401Cys | missense_variant | 7/10 | NM_005572.4 | ENSP00000503633.1 |
Frequencies
GnomAD3 genomes 0.000131 AC: 20AN: 152248Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000763 AC: 19AN: 249138Hom.: 0 AF XY: 0.0000890 AC XY: 12AN XY: 134818
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GnomAD4 exome AF: 0.0000671 AC: 98AN: 1459590Hom.: 0 Cov.: 34 AF XY: 0.0000578 AC XY: 42AN XY: 726138
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GnomAD4 genome 0.000131 AC: 20AN: 152248Hom.: 0 Cov.: 32 AF XY: 0.0000807 AC XY: 6AN XY: 74386
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:17Benign:1Other:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:8Other:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Oct 14, 2022 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jan 01, 2023 | LMNA: PS1, PM6:Supporting, PP4, PS3:Supporting, BS1 - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Apr 05, 2019 | The p.Arg401Cys variant in LMNA has been reported in 1 individual with Emery Dreifuss muscular dystrophy who carried a second LMNA variant (p.Thr150fs), which was also present in the father who suffered sudden cardiac death. The p.Arg401Cys variant was also identified in the reportedly unaffected mother and sister (Hanisch 2002, Vytopil 2002, Muchir 2004, Emerson 2009). This variant was also identified in 2 individuals with DCM (one with neonatal onset), segregated with disease in 1 affected relative (Chami 2014, LMM data) and has also been reported in ClinVar (Variation ID 48035).Clinvar: VUS (6 submitters), LP (Montreal heart institute). It has been identified in 6/34400 of Latino chromosomes and 11/126264 of European chromosomes by the Genome Aggregation Consortium (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs61094188). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Arg401Cys variant is uncertain. - |
| not provided, no classification provided | literature only | Epithelial Biology; Institute of Medical Biology, Singapore | - | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jul 17, 2024 | Observed in trans with another LMNA variant (c.447insC) in a different individual with EDMD and was found to be inherited from a parent without neuromuscular disease (PMID: 19524666); Observed in two siblings with dilated cardiomyopathy who may or may not have had additional variants in other cardiomyopathy-related genes (PMID: 25448463); 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: 23977161, 12376891, 25210889, 15843404, 23861362, 16584978, 24503780, 24623722, 28531892, 27532257, 17107595, 15372542, 30420677, 31428229, 34426522, 32880476, 31383942, 32793522, 34240052, 32041611, 32376792, 30564623, 25448463, 12467752, 19524666, 37652022, 10939567) - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | May 17, 2018 | - - |
| Uncertain significance, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
| Uncertain significance, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Jun 12, 2023 | - - |
Cardiomyopathy Uncertain:2
| Uncertain significance, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Sep 30, 2015 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Feb 15, 2023 | This missense variant replaces arginine with cysteine at codon 401 of the lamin A/C protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). This variant is located in the C-terminal region of the protein that mediates interaction with many protein binding partners. Functional studies have shown that for the most part, this variant does not adversely affect protein interaction, although interaction with some binding partners may be affected (PMID: 23977161, 24623722, 32698523). This variant has been reported in an individual affected with Hauptmann-Thannhauser muscular dystrophy (PMID: 12376891), in a family and an unrelated individual affected with dilated cardiomyopathy (PMID: 25448463, 32880476), and in another individual affected with congenital heart defects (PMID: 32793522). This variant has also been identified in 22/280520 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Primary familial dilated cardiomyopathy Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute | Jul 10, 2020 | PM2;PP1 (internal data); PP2;PP3;PS4_supp - |
not specified Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 22, 2024 | Variant summary: LMNA c.1201C>T (p.Arg401Cys) results in a non-conservative amino acid change in 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 7.6e-05 in 249138 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in LMNA causing Cardiomyopathy (7.6e-05 vs 0.00025), allowing no conclusion about variant significance. c.1201C>T has been reported in the literature in as compound heterozygous genotype in individuals affected with autosomal recessive Emery-Dreifuss muscular dystrophy 3 and unaffected individuals (Vytopil_2002, Emerson_2009) or as heterpozygous genotype in an individual affected with clinical features of ventricular septal defect, malignant arrhythmias, (left ventricular non-compaction with LV dysfunction and dilated cardiomyopathy (Baban_2020). These data indicate that the variant may be associated with disease with incomplete penetrance. At least one publication reports experimental evidence evaluating an impact on protein function and the data indicates that the variant results in impaired emerinlamin A/C interaction, enhanced cell proliferation, collagen-dependent adhesion, larger numbers of filopodia and smaller cell spread size, and elevated cell migration, speed and polarization (Emerson_2009). The following publications have been ascertained in the context of this evaluation (PMID: 32793522, 19524666, 12467752, 30420677). ClinVar contains an entry for this variant (Variation ID: 48035). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. - |
Charcot-Marie-Tooth disease Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Molecular Genetics Laboratory, London Health Sciences Centre | - | - - |
Emery-Dreifuss muscular dystrophy Uncertain:1
| Uncertain significance, criteria provided, single submitter | research | Biesecker Lab/Clinical Genomics Section, National Institutes of Health | Jun 24, 2013 | - - |
Catecholaminergic polymorphic ventricular tachycardia 1 Uncertain:1
| Uncertain significance, no assertion criteria provided | clinical testing | Blueprint Genetics | Aug 19, 2014 | - - |
Primary dilated cardiomyopathy Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Sep 23, 2024 | This missense variant replaces arginine with cysteine at codon 401 of the lamin A/C protein. Computational prediction tools indicate that this variant's impact on protein structure and function is inconclusive. This variant is located in the C-terminal region of the protein that mediates interaction with many protein binding partners. Functional studies have shown that for the most part, this variant does not adversely affect protein interaction, although interaction with some binding partners may be affected (PMID: 23977161, 24623722, 32698523). Another functional study using myoblasts derived from a carrier individual has shown that this variant may interfere with localization of desmin to the nuclear envelope (PMID: 38247853). This variant has been reported in three individuals affected with dilated cardiomyopathy (PMID: 25448463, 32880476, 37904629). It has also been reported in one individual affected with Hauptmann-Thannhauser muscular dystrophy (PMID: 12376891), in one individual affected with congenital heart defects (PMID: 32793522), and in one individual affected with congenital muscular dystrophy (PMID: 34240052). This variant has also been identified in 22/280520 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Hutchinson-Gilford syndrome;C0410190:Emery-Dreifuss muscular dystrophy 2, autosomal dominant;C0796031:Dilated cardiomyopathy-hypergonadotropic hypogonadism syndrome;C1449563:Dilated cardiomyopathy 1A;C1720860:Familial partial lipodystrophy, Dunnigan type;C1854154:Charcot-Marie-Tooth disease type 2B1;C1857829:Heart-hand syndrome, Slovenian type;C2750035:Emery-Dreifuss muscular dystrophy 3, autosomal recessive;C2750785:Congenital muscular dystrophy due to LMNA mutation;C5399785:Mandibuloacral dysplasia with type A lipodystrophy;C5676942:Restrictive dermopathy 2 Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Mar 06, 2024 | - - |
Cardiovascular phenotype Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 28, 2023 | The p.R401C variant (also known as c.1201C>T), located in coding exon 7 of the LMNA gene, results from a C to T substitution at nucleotide position 1201. The arginine at codon 401 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant was originally reported in an individual with skeletal, muscular, and cardiac findings, as well as in his unaffected mother and sister (Hanisch F et al. Nervenarzt, 2002 Oct;73:1004-11; Vytopil M et al. Neuromuscul. Disord., 2002 Dec;12:958-63). This variant has also been detected in individuals with Emery-Dreifuss muscular dystrophy, including one case of a compound heterozygote who also had an LMNA truncating variant (Muchir A et al. Muscle Nerve, 2004 Oct;30:444-50; Emerson LJ et al. Biochim. Biophys. Acta, 2009 Aug;1792:810-21). In addition, this variant has been described in individuals and genetic testing cohorts with dilated cardiomyopathy, including two affected siblings, but clinical details were limited (Pugh TJ et al. Genet. Med., 2014 Aug;16:601-8; Chami N et al. Can J Cardiol, 2014 Dec;30:1655-61; Walsh R et al. Genet. Med., 2017 02;19:192-203; Verdonschot JAJ et al. Circ Genom Precis Med, 2020 10;13:476-487). Finally, this variant was reported as maternally inherited in a left ventricular non-compaction (LVNC) case with a maternal family history of atrial fibrillation and sudden cardiac death, but whose carrier mother was apparently unaffected (Baban A et al. Front Pediatr, 2020 Jul;8:374). Functional studies have suggested this alteration may impact protein function; however, the clinical relevance of those results is unclear (Muchir A et al. Muscle Nerve, 2004 Oct;30:444-50; Capanni C et al. Exp. Cell Res., 2003 Nov;291:122-34; Yang L et al. PLoS ONE, 2013 Aug;8:e71850; Angori S et al. Cell. Physiol. Biochem., 2017 May;42:169-184). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Charcot-Marie-Tooth disease type 2 Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 31, 2024 | - - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
CardioboostCm
Uncertain
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Pathogenic
.;.;.;D;.;.;.;.;T
Eigen
Uncertain
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
Uncertain
D
MutationAssessor
Uncertain
M;.;M;M;M;.;.;.;.
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D;D;D;D;D;D;D;D
REVEL
Uncertain
Sift
Uncertain
D;D;D;D;D;D;D;D;D
Sift4G
Uncertain
D;D;D;D;D;D;D;D;D
Polyphen
D;.;D;D;.;.;D;.;.
Vest4
MVP
MPC
1.2
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at