1-156137667-G-A
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Variant summary
Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2PM5PP2PP3_ModeratePP5_Very_Strong
The NM_170707.4(LMNA):c.1622G>A(p.Arg541His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000143 in 1,401,790 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. R541G) has been classified as Pathogenic.
Frequency
Genomes: 𝑓 0.0 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
LMNA
NM_170707.4 missense
NM_170707.4 missense
Scores
14
5
1
Clinical Significance
Conservation
PhyloP100: 8.39
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 Pathogenic. Variant got 17 ACMG points.
PM1
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 14 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 chr1-156137666-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 48046.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
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, 0.866
PP5
Variant 1-156137667-G-A is Pathogenic according to our data. Variant chr1-156137667-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 66860.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-156137667-G-A is described in Lovd as [Pathogenic]. Variant chr1-156137667-G-A is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| LMNA | NM_170707.4 | c.1622G>A | p.Arg541His | missense_variant | 10/12 | ENST00000368300.9 | NP_733821.1 | |
| LMNA | NM_005572.4 | c.1622G>A | p.Arg541His | missense_variant | 10/10 | ENST00000677389.1 | NP_005563.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| LMNA | ENST00000368300.9 | c.1622G>A | p.Arg541His | missense_variant | 10/12 | 1 | NM_170707.4 | ENSP00000357283.4 | ||
| LMNA | ENST00000677389.1 | c.1622G>A | p.Arg541His | missense_variant | 10/10 | NM_005572.4 | ENSP00000503633.1 |
Frequencies
GnomAD3 genomes 0.00 AC: 0AN: 152188Hom.: 0 Cov.: 32 FAILED QC
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GnomAD4 exome AF: 0.00000143 AC: 2AN: 1401790Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 691530
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GnomAD4 genome 0.00 AC: 0AN: 152306Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74486
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:13Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:4Other:1
| not provided, no classification provided | literature only | Epithelial Biology; Institute of Medical Biology, Singapore | - | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Oct 15, 2021 | The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). At least one other missense variant at this codon is considered to be pathogenic or likely pathogenic, suggesting this variant may also cause disease. This variant has been identified heterozygous in multiple unrelated individuals with Emery-Dreifuss Muscular Dystrophy (EDMD), Muscular Dystrophy (MD) and Dilated Cardiomyopathy (DCM), suggesting dominant inheritance. Computational tools predict that this variant is damaging. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jun 19, 2018 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 21, 2022 | Functional study shows that this variant has a moderate effect on the structural stability of protein; however, it is not known whether these findings are biological or clinically relevant in vivo (Scharner et al., 2013); 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: 18646565, 23183350, 24375749, 18564364, 12057196, 27532257, 28152038, 22186027, 10612827, 29764566, 24623722, 14684700) - |
| Likely pathogenic, no assertion criteria provided | clinical testing | Stanford Center for Inherited Cardiovascular Disease, Stanford University | Jun 13, 2012 | Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. LMNA p.Arg541His Based on the data reviewed below we consider this variant to be likely disease causing. This is primarily due to strong segregation data in one Russian family and multiple variants at this location that are associated with LMNA-specific phenotypes. This variant is located in exon 10 of the LMNA gene. The arginine at codon 541 is replaced by histidine, an amino acid with similar properties. Based on protein sequence alignment in available vertebrate species, this amino acid position is absolutely conserved. Surrounding residues are highly conserved as well. In-silico analysis predicts the variant to be “possibly damaging” by PolyPhen-2 and “tolerated” by SIFT. This variant has been seen previously in at least 2 unrelated individuals with LMNA phenotypes. Vytopil et al. found p.R541H in a 20-year-old patient with Emery-Dreifuss muscular dystrophy who had humeroperoneal myopathy, a rigid spine, and arrhythmia (Vytopil et al. 2003 J Med Genet 40:e132). In a study by Rudenskaya et al., p.R541H segregated with disease in 7 members of a Russian family with dilated cardiomyopathy (DCM) with conduction defects (Rudenskaya et al. 2008 Clin Genet 74:127-133) and multiple sudden cardiac deaths. The proband was a female with DCM, normal CK, atrial fibrillation, AV block, and PVCs, diagnosed at age 19. Her affected female cousin died suddenly at age 16 of pulmonary thromboembolism and carried the same variant, as did another affected male cousin who died suddenly at age 14, and her affected brother who died suddenly at age 19. Her obligate carrier mother, obligate carrier uncle, and obligate carrier aunt were affected and each died suddenly before age 40 (ages 38, 35 and 22). A number of alterations at the same codon (but with substitution of a different amino acid) have also been reported in the published literature. Forissier et al. detected p.R541C (Arg to Cys) in a French father and daughter who exhibited an atypical form of dilated cardiomyopathy with global hypokinesia and unexplained left ventricular aneurysm revealed after ventricular rhythm disturbances without atrio-ventricular block. The father presented with VT at age 22, developed LBBB at age 27, and had a heart transplant at age 44. The p.R541C mutation was shown to be de novo in the father—after both of his parents and all 10 of his siblings were phenotyped by EKG, echo, and CK, and also genotyped; there was no prior family history of congestive heart failure or sudden death. His daughter developed dyspnea and PVCs at age 20 and had nonsustained VT at age 25 (Forissier et al. 2003 Eur J Heart Fail 5(6):821-5). Likewise, Hookana et al. detected p.R541C in a Finnish family in which a 40-year-old mother was resuscitated from VF that occurred while she was playing volleyball, and subsequently found to have local hypokinesia and thinning of the LV with otherwise normal overall chamber size and function. The proband’s daughter died suddenly at age 14 while standing on the street with her friends, without any prior cardiac symptoms, and was shown on autopsy to have localized thinning and fibrosis of the LV (Hookana et al. 2008 J Cardiovasc Electrophysiol 19:743-747). The R541C variant was detected only in these two family members, and was found to be de novo in the proband (paternity for the proband was genetically confirmed). Sixteen first- and second-degree family members, including the proband’s parents, also had normal echocardiograms. Malek et al. found p.R541G (Arg to Gly) in a 23-year-old male with a family history of DCM and sudden death who presented with inferolateral wall thinning and regional akinesis with evidence of mid-myocardial fibrosis on MRI. - |
Primary dilated cardiomyopathy Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Apr 29, 2015 | The p.Arg541His variant in LMNA has been reported in 5 individuals with variable phenotypes consistent with a laminopathy (phenotypes included EDMD, DCM, AFib, AV block, and arrhythmia; Vytopil 2003, Rankin 2006, Astejada 2007, Rudenskaya 2 008, van Rijsingen 2013). Notably, cardiac phenotypes presented within the first to second decade of life (Vytopil 2003, Rankin 2006, Rudenskaya 2008). This var iant was found to segregate with isolated DCM in 5 affected relatives from 1 fam ily (Rudenskaya 2008). In addition, it occurred de novo in an individual with te enage-onset DCM with LVH and conduction disease (LMM unpublished data). This var iant has been identified in 2/9136 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org/; dbSNP rs61444459). Computati onal prediction tools and conservation analysis also support pathogenicity as do other amino acid alterations at this position (p.Arg541Ser, p.Arg541Cys, p.Arg5 41Gly, p.Arg541Pro) that have been identified in individuals with laminopathy ph enotypes. In summary, this variant meets our criteria to be classified as pathog enic for LMNA associated disease in an autosomal dominant manner (http://www.par tners.org/personalizedmedicine/LMM) based on de novo occurrence and segregation studies. - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Center for Human Genetics, University of Leuven | Feb 09, 2017 | ACMG score likely pathogenic - |
Dilated cardiomyopathy 1A Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Jan 01, 2019 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Juno Genomics, Hangzhou Juno Genomics, Inc | - | PM2_Supporting+PP3_Moderate+PM5_Strong+PS4_Moderate+PP1_Moderate - |
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 histidine, which is basic and polar, at codon 541 of the LMNA protein (p.Arg541His). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with Emery-Dreifuss muscular dystrophy and dilated cardiomyopathy (PMID: 10612827, 14675861, 14684700, 18564364, 18646565, 23183350, 27532257). ClinVar contains an entry for this variant (Variation ID: 66860). 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%. This variant disrupts the p.Arg541 amino acid residue in LMNA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22186027, 24623722). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
LMNA-related disorder Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego | - | This variant has been previously reported as a heterozygous change in patients with LMNA-related disorders including cardiomyopathy, cardiovascular disease, and muscular dystrophy (PMID: 14684700; 28152038; 27532257). Missense variation at nearby nucleotides [c.1621C>T (p.Arg541Cys), c.1621C>G (p.Arg541Gly), and c.1621C>A (p.Arg541Ser)] have been previously reported in individuals with dilated cardiomyopathy and apical left ventricular aneurysm (PMID: 14675861, 18031519, 21085127, 16061563). The c.1622G>A (p.Arg541His) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.0019% (3/160368) and thus is presumed to be rare. The c.1622G>A (p.Arg541His) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, the c.1622G>A (p.Arg541His) variant is classified as Pathogenic. - |
Congenital muscular dystrophy Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Mar 14, 2024 | - - |
Cardiovascular phenotype Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 20, 2012 | ​The p.R541H suspected pathogenic variant (also known as c.1622G>A) is located in coding exon 10 of the LMNA gene. This alteration results from a G to A substitution at nucleotide position 1622. The arginine at codon 541 is replaced by histidine, an amino acid with similar properties. This variant was observed in a male proband tested in our laboratory who is affected with left ventricular noncompaction (LVNC), low ejection fraction, ventricular tachycardia, type I diabetes, history of embolic stroke and toe walking. The variant was absent in the proband's brother who is affected with LVNC. In one study, p.R541H was detected in a patient with Emery-Dreifuss muscular dystrophy who had humoperoneal myopathy, a rigid spine, and arrhythmia (Vytopil et al. 2003 J Med Genet 40:e132). In another study, p.R541H segregated with disease in a family with dilated cardiomyopathy (DCM) with conduction defects (Rudenskaya et al. 2008 Clin Genet 74:127-133). A number of alterations at the same codon have also been reported in the published literature. In one study, p.R541C was detected in a father and daughter who exhibited an atypical form of dilated cardiomyopathy with unexplained left ventricle aneurysm revealed by ventricular rhythm disturbances without atrio-ventricular block. The p.R541C mutation was apparently de novo in the father (Forissier et al. 2003 Eur J Heart Fail 5(6):821-5). In another study, the p.R541G was described in a 23-year-old patient who presented with inferolateral wall thinning and akinesis with evidence of mid-myocardial fibrosis on MRI. Notably, a marked hypertrabelculation in the dysfunctional regions was also seen on cardiac MRI (Malek et al. 2011 J Hum Genet 56:83-86). Another study detected the p.R541P mutation in a 13-year-old male who had DCM with elevated CK levels. The authors confirmed that p.R541P was a de novo mutation in this individual (van Tintelen et al. 2007 Am Heart J 154:1130-9). This variant was not reported in population-based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP) and 1000 Genomes Project. Based on protein sequence alignment in available vertebrate species, this amino acid position is highly conserved. In addition, this alteration is predicted to be possibly damaging and tolerated by PolyPhen and SIFT in silico analyses, respectively. Based on the majority of available evidence to date, this variant is likely to be pathogenic; however, its clinical significance remains unclear. - |
Hutchinson-Gilford syndrome Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | DASA | Feb 14, 2022 | The c.1622G>A;p.(Arg541His) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID: 66860; PMID: 24623722; 24375749; 18564364; 18646565; 16965317; 14684700; 14675861) - PS4. The variant is present at low allele frequencies population databases (rs61444459 - gnomAD 0.0001871%; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2_supporting. Pathogenic missense variant in this residue have been reported (Clinvar ID: 66861; PMID: 14675861; 16061563) - PM5. The variant co-segregated with disease in multiple affected family members (PMID: 18564364) - PP1. In summary, the currently available evidence indicates that the variant is likely pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
CardioboostCm
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Pathogenic
.;.;D;.;.;.;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;D;D;D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Uncertain
M;.;M;M;.;.;.
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;.;D;D;D;D;D
REVEL
Pathogenic
Sift
Uncertain
D;.;D;D;D;D;D
Sift4G
Uncertain
D;T;D;D;D;D;D
Polyphen
D;.;D;.;.;D;.
Vest4
MutPred
Gain of ubiquitination at K542 (P = 0.0475);.;Gain of ubiquitination at K542 (P = 0.0475);Gain of ubiquitination at K542 (P = 0.0475);.;.;.;
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