1-156138719-C-T
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Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 3P and 8B. PM5PP2BP4_StrongBS2
The NM_170707.4(LMNA):c.1930C>T(p.Arg644Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00201 in 1,613,372 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign 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. R644H) has been classified as Likely benign.
Frequency
Genomes: 𝑓 0.0011 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0021 ( 13 hom. )
Consequence
LMNA
NM_170707.4 missense
NM_170707.4 missense
Scores
2
13
4
Clinical Significance
Conservation
PhyloP100: 3.06
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 Likely_benign. Variant got -5 ACMG points.
PM5
Other missense variant is known to change same aminoacid residue: Variant chr1-156138720-G-A is described in Lovd as [Pathogenic].
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.
BP4
Computational evidence support a benign effect (MetaRNN=0.063878536).
BS2
High Homozygotes in GnomAdExome4 at 13 SD gene
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| LMNA | NM_170707.4 | c.1930C>T | p.Arg644Cys | missense_variant | 11/12 | ENST00000368300.9 | NP_733821.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| LMNA | ENST00000368300.9 | c.1930C>T | p.Arg644Cys | missense_variant | 11/12 | 1 | NM_170707.4 | ENSP00000357283.4 |
Frequencies
GnomAD3 genomes 0.00114 AC: 174AN: 152032Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00119 AC: 295AN: 248536Hom.: 1 AF XY: 0.00135 AC XY: 182AN XY: 134956
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GnomAD4 exome AF: 0.00210 AC: 3073AN: 1461222Hom.: 13 Cov.: 32 AF XY: 0.00209 AC XY: 1519AN XY: 726932
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GnomAD4 genome 0.00114 AC: 174AN: 152150Hom.: 0 Cov.: 32 AF XY: 0.000981 AC XY: 73AN XY: 74392
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:12Benign:12Other:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not specified Uncertain:2Benign:4
| Likely benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jan 26, 2016 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 30, 2024 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute | Mar 31, 2017 | - - |
| Benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | Feb 06, 2024 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jul 12, 2021 | The p.Arg644Cys variant in LMNA has been detected by our laboratory in 7 individuals with cardiomyopathy (2 with DCM, 1 with LVNC, 2 with HCM, 1 with an unspecified cardiomyopathy, and 1 with VFib and a T-wave inversion). Four of these patients had a very early age at onset (range birth to 7 years) and no family history, which is atypical for LMNA variants. The p.Arg644Cys variant has also been identified in a large number of individuals (>20) with a diverse range of clinical features consistent with laminopathy, isolated cardiomyopathy (DCM, ARVC, HCM) or Hallermann-Streiff syndrome, a rare genetic disorder with clinical overlap with some laminopathies (Speckman 2000 PMID: 10739751, Genschel 2001 PMID: 11180602, Csoka 2004 PMID: 15060110, Mercuri 2005 PMID: 15770669, Muntoni 2006 PMID: 16585054, Rankin 2008 PMID: 18478590, Pasotti 2008 PMID: 18926329, Perrot 2009 PMID: 18795223, Møller 2009 PMID: 19875404, Kortum 2011 PMID: 22570643, Scharner 2011 PMID: 20848652, Larsen 2012 PMID: 22177269, Quarta 2012 PMID: 22199124, Vasli 2012 PMID: 22526018, Hoyer 2014 PMID: 25025039). In addition, one study reported non-segregation with disease in 2 families (Mercuri 2005 PMID: PMID: 15770669). This variant has also been identified in 0.2% (251/126914) of European chromosomes, including 1 homozygote, chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein; however, in vitro functional studies indicate the variant may affect nuclear morphology (Csoka 2004 PMID: 15060110). In summary, the lack of segregation with disease, its population frequency, and the wide-spectrum of observed phenotypes sugests that the p.Arg644Cys variant is likely benign. ACMG/AMP Criteria applied: BS1, BS4. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Aug 25, 2017 | The R644C variant of uncertain significance in the LMNA gene has been reported multiple times in association with LMNA-related disorders, and demonstrates a wide phenotypic spectrum, variable severity, incomplete penetrance, and non-segregation (Genschel et al., 2001; Csoka et al., 2004; Mercuri et al., 2005; Muntoni et al., 2006; Rankin et al., 2008; Pasotti et al., 2008; Moller et al., 2009; Perrot et al., 2009; Scharner et al., 2011; Quarta et al., 2012; Vasli et al., 2012; Larsen et al., 2012; Hoyer et al., 2014; Cann et al., 2016). The R644C variant has been identified in individuals with isolated cardiomyopathy, laminopathies, Hallermann-Streiff syndrome, or Hutchinson-Gilford progeria syndrome, and also in asymptomatic relatives. Additionally, two studies reported that the R644C variant did not segregate with disease in two unrelated families (Mercuri et al., 2005; Muntoni et al., 2006). The Exome Aggregation Consortium (ExAC) reports R644C was observed in 106/63,724 alleles from individuals of Non-Finnish European and 27/16,410 alleles from individuals of South Asian ancestry, including one homozygote, indicating it may be a rare benign variant in these populations (Lek et al., 2016). It has been suggested that the extreme phenotypic variability caused by this pleiotropic LMNA variant could be due to either an altered methylation pattern or abnormal post-translational processing of prelamin A because R644C is located at the C-terminal end of lamin A/C close to the endoproteolytic cleavage site (Perrot et al., 2009; Capell et al., 2006). The R644C 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. Additionally, this substitution occurs at a position that is conserved in mammals. Nevertheless, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. - |
not provided Uncertain:2Benign:2Other:1
| Uncertain significance, no assertion criteria provided | provider interpretation | Stanford Center for Inherited Cardiovascular Disease, Stanford University | Jan 03, 2017 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Oct 01, 2024 | LMNA: BS2 - |
| Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Mar 08, 2022 | The LMNA c.1930C>T; p.Arg644Cys variant (rs142000963) is reported in the literature in individuals affected with cardiomyopathy and laminopathy LMNA-related disorders, including variable phenotypes, severity, penetrance, and segregation (Mercuri 2005, Muntoni 2006, Rankin 2008, Seidelmann 2017, Stehlikova 2017). This variant is also reported in ClinVar (Variation ID: 14527), and is found in the general population with an overall allele frequency of 0.12% (334/279890 alleles, including a single homozygote) in the Genome Aggregation Database. The arginine at codon 644 is highly conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.608). In vitro functional analyses of the variant protein show no significant effect on gap junctions or nuclear lamina integrity (De Vos 2011, Sun 2010), but other studies demonstrated impaired cleavage of lamin A (Barrowman 2012) and nuclear aberrations (Csoka 2004). While the high population frequency and lack of segregation with disease suggest that this is likely a benign variant, given the conflicting clinical and functional data, the significance of the p.Arg644Cys variant is uncertain at this time. References: Barrowman J et al. Requirements for efficient proteolytic cleavage of prelamin A by ZMPSTE24. PLoS One. 2012;7(2):e32120. PMID: 22355414. Csoka AB et al. Novel lamin A/C gene (LMNA) mutations in atypical progeroid syndromes. J Med Genet. 2004 Apr;41(4):304-8. PMID: 15060110. De Vos WH et al. Repetitive disruptions of the nuclear envelope invoke temporary loss of cellular compartmentalization in laminopathies. Hum Mol Genet. 2011 Nov 1;20(21):4175-86. PMID: 21831885. Mercuri E et al. Extreme variability of skeletal and cardiac muscle involvement in patients with mutations in exon 11 of the lamin A/C gene. Muscle Nerve. 2005 May;31(5):602-9. PMID: 15770669. Muntoni F et al. Disease severity in dominant Emery Dreifuss is increased by mutations in both emerin and desmin proteins. Brain. 2006 May;129(Pt 5):1260-8. PMID: 16585054. Rankin J et al. Extreme phenotypic diversity and nonpenetrance in families with the LMNA gene mutation R644C. Am J Med Genet A. 2008 Jun 15;146A(12):1530-42. PMID: 18478590. Seidelmann SB et al. Application of Whole Exome Sequencing in the Clinical Diagnosis and Management of Inherited Cardiovascular Diseases in Adults. Circ Cardiovasc Genet. 2017 Feb;10(1):e001573. PMID: 28087566. Stehlikova K et al. Muscular dystrophies and myopathies: the spectrum of mutated genes in the Czech Republic. Clin Genet. 2017 Mar;91(3):463-469. PMID: 27447704. Sun LP et al. Connexin 43 remodeling induced by LMNA gene mutation Glu82Lys in familial dilated cardiomyopathy with atrial ventricular block. Chin Med J (Engl). 2010 Apr 20;123(8):1058-62. PMID: 20497714. - |
| Likely benign, criteria provided, single submitter | research | Biesecker Lab/Clinical Genomics Section, National Institutes of Health | Jun 24, 2013 | - - |
| not provided, no classification provided | literature only | Epithelial Biology; Institute of Medical Biology, Singapore | - | - - |
Charcot-Marie-Tooth disease Pathogenic:1Uncertain:1
| Likely pathogenic, no assertion criteria provided | research | Dept. of Medical Genetics, Telemark Hospital Trust, Telemark Hospital Trust | Nov 01, 2013 | Observed in two induviduals from two different families. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Molecular Genetics Laboratory, London Health Sciences Centre | - | - - |
Dilated cardiomyopathy 1A Uncertain:2
| Uncertain significance, criteria provided, single submitter | clinical testing | Equipe Genetique des Anomalies du Developpement, Université de Bourgogne | Nov 21, 2018 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | May 09, 2019 | This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PP3,PP5. - |
Primary dilated cardiomyopathy Uncertain:1Benign:1
| Uncertain significance, no assertion criteria provided | research | CSER _CC_NCGL, University of Washington | Jun 01, 2014 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Sep 27, 2024 | - - |
Cardiomyopathy Benign:2
| Benign, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Sep 12, 2019 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Mar 16, 2018 | - - |
Variant of unknown significance Uncertain:1
| Uncertain significance, no assertion criteria provided | literature only | OMIM | Nov 01, 2009 | - - |
LMNA-related disorder Uncertain:1
| Uncertain significance, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Mar 28, 2024 | The LMNA c.1930C>T variant is predicted to result in the amino acid substitution p.Arg644Cys. The p.Arg644Cys variant has been identified in many unrelated individuals in association with different types of laminopathies, suggesting variable expressivity and incomplete penetrance (Rankin et al. 2008. PubMedID: 18478590). The phenotypic spectrum includes Emery-Dreifuss muscular dystrophy (Mercuri et al. 2005. PubMedID: 15770669), dilated cardiomyopathy (Genschel et al. 2001. PubMedID: 11180602; Parent et al. 2015. PubMedID: 25873806), and one patient with atypical progeria syndrome (Csoka et al. 2004. PubMedID: 15060110). However, the segregation data for the p.Arg644Cys variant is not conclusive (Mercuri et al. 2005. PubMedID: 15770669; Muntoni et al. 2006. PubMedID: 16585054). One study indicated that fibroblasts with the the p.Arg644Cys variant displayed normal nuclear morphology (van Tienen. 2019. PubMed ID: 30420677). This variant is reported in 0.20% of alleles in individuals of European (Non-Finnish) descent in gnomAD, including 1 homozygote. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Familial partial lipodystrophy, Dunnigan type Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | New York Genome Center | Mar 20, 2023 | - - |
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 | Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago | Mar 30, 2021 | LMNA NM_170707.3 exon 11 p.Arg644Cys (c.1930C>T): This variant has been reported in the literature in several individuals with a wide spectrum of laminopathy phenotypes, including cardiomyopathies, cardioskeletal myopathies, atypical progeria, lipodystrophy, neuropathy, arthrogryposis, and hepatic stenosis (Genschel 2000 PMID:11180602, Csoka 2004 PMID:15060110, Mercuri 2005 PMID:15770669, Passotti 2008 PMID:18926329, Rankin 2008 PMID:18478590, Perrot 2009 PMID:18795223, Scharner 2011 PMID:20848652, Kortum 2011 PMID:22570643, De Vos 2011 PMID:21831885, Larsen 2012 PMID:22177269, Quarta 2013 PMID:22199124, Hoyer 2014 PMID:25025039, Parent 2015 PMID:25873806, Stehlikova 2017 PMID:27447704). This variant segregated with disease in at least 3 individuals, but did not segregate with disease in at least two others (Mercuri 2005 PMID:15770669, Parent 2015 PMID:25873806). This variant was also present in several asymptomatic relatives, indicating that it may have reduced penetrance. However, this variant is also present in 0.1% (251/126914) of European alleles in the Genome Aggregation Database, including one homozygote (https://gnomad.broadinstitute.org/variant/1-156108510-C-T), suggesting that it may be a common benign variant. This variant is present in ClinVar with conflicting interpretations (Variation ID:14527). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In vitro functional studies have demonstrated partial inhibition of ZMPSTE24 cleavage with this variant (Barrowman 2012 PMID:22355414). However, multiple expression studies in fibroblast cultures of individuals with this variant have shown no effect on gap junctions and normal nuclear morphology (Sun 2010 PMID:20497714, De Vos 2011 PMID:21831885, van Tienen 2019 PMID:30420677). However, these studies may not accurately represent in vivo biological function. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. - |
Charcot-Marie-Tooth disease type 2 Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 31, 2024 | - - |
Monogenic diabetes Benign:1
| Benign, criteria provided, single submitter | research | Personalized Diabetes Medicine Program, University of Maryland School of Medicine | Nov 02, 2018 | ACMG criteria: BS4 (lack of segregation in 15770669, 16585054), BS1 (0.2% MAF in EurNF), BS2 (two homozygotes in gnomAD), PS3 (reduces cleavage efficacy of prelaminA tail: 28663758, 22355414) [REVEL 0.608, PP3 (8), BP4 (2) = conflicting evidence, not using] = Benign - |
Cardiovascular phenotype Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 05, 2021 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Uncertain
.;T;.;.;T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D;D;D
M_CAP
Uncertain
D
MetaRNN
Benign
T;T;T;T;T
MetaSVM
Uncertain
D
MutationAssessor
Benign
.;L;.;.;.
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N;N;N;N
REVEL
Uncertain
Sift
Uncertain
D;D;D;D;D
Sift4G
Uncertain
D;D;D;D;D
Polyphen
D;D;.;.;.
Vest4
MVP
MPC
0.96
ClinPred
T
GERP RS
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gMVP
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Name
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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