Submissions for variant NM_170707.4(LMNA):c.1622G>A (p.Arg541His)

dbSNP: rs61444459

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000221013	SCV000271391	pathogenic	Primary dilated cardiomyopathy	2015-04-29	criteria provided, single submitter	clinical testing	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 In addition, it occurred de novo in an individual with te enage-onset DCM with LVH and conduction disease (LMM unpublished data).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.
Invitae	RCV000230467	SCV000291554	pathogenic	Charcot-Marie-Tooth disease type 2	2024-01-15	criteria provided, single submitter	clinical testing	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.
GeneDx	RCV000057344	SCV000292601	pathogenic	not provided	2022-01-21	criteria provided, single submitter	clinical testing	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)
Ambry Genetics	RCV000246865	SCV000317868	likely pathogenic	Cardiovascular phenotype	2012-11-20	criteria provided, single submitter	clinical testing	​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.
Eurofins Ntd Llc (ga)	RCV000057344	SCV000338484	pathogenic	not provided	2018-06-19	criteria provided, single submitter	clinical testing
Center for Human Genetics, University of Leuven	RCV000221013	SCV000579530	likely pathogenic	Primary dilated cardiomyopathy	2017-02-09	criteria provided, single submitter	clinical testing	ACMG score likely pathogenic
Institute of Human Genetics, University of Leipzig Medical Center	RCV001262710	SCV001440679	pathogenic	Dilated cardiomyopathy 1A	2019-01-01	criteria provided, single submitter	clinical testing
DASA	RCV001836636	SCV002097281	likely pathogenic	Hutchinson-Gilford syndrome	2022-02-14	criteria provided, single submitter	clinical testing	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.
Athena Diagnostics Inc	RCV000057344	SCV002771307	likely pathogenic	not provided	2021-10-15	criteria provided, single submitter	clinical testing	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.
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV003335086	SCV004046139	pathogenic	LMNA-Related Disorders		criteria provided, single submitter	clinical testing	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.
Epithelial Biology; Institute of Medical Biology, Singapore	RCV000057344	SCV000088457	not provided	not provided		no assertion provided	not provided
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000057344	SCV000280180	likely pathogenic	not provided	2012-06-13	no assertion criteria provided	clinical testing	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. He had previously undergone ablation for AV nodal re-entrant tachycardia. There was marked hypertrabelculation in the dysfunctional regions as seen on cardiac MRI. His affected sister (who had sinus bradycardia and atrial and ventricular arrhythmias) also carried the variant. His affected father and aunt had died suddenly, and the aunt had LV aneurysm. These researchers transfected mouse myoblasts with the mutant gene, and report that it produced abnormal lamin aggregates (Malek et al. 2011 J Hum Genet 56:83-86). Van Tintelen et al. detected a p.R541K mutation (Arg to Lys) in a 13-year-old male who had DCM, intraventricular conduction delay, nonsustained VT, and mildly elevated CK levels. He had a heart transplant at age 14. The authors confirmed through family member testing that p.R541K was a de novo mutation in this individual. Paternity was genetically confirmed, and the patient’s parents had apparently normal phenotypes (van Tintelen et al. 2007 Am Heart J 154:1130-9). Sylvius et al. (2005) found p.R541S in a Canadian family with suspected autosomal dominant transmission. Scharner et al. (2011) reported R541S in a male from the US or Canada diagnosed at age 13 with familial DCM and congestive heart failure requiring transplantation. (It is unclear if this is the same family.) There was a family history of various degrees of DCM and limb-girdle muscular dystrophy, plus loss of adipose tissue in females. Scharner et al. (2011) found R541P in a female patient from the US or Canada with atrial fibrillation and limb-girdle muscular dystrophy diagnosed in childhood. She had a daughter with limb-girdle muscular dystrophy and a son with Emery-Dreifuss muscular dystrophy. Astejada et al. (2007) report R541H in a Japanese muscular dystrophy patient. This may not be a comprehensive list. In total the variant has not been seen in ~6850 individuals from published reports and publicly available population datasets. According to Ambry this variant was not reported in population-based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), and 1000 Genomes Project. There is no variation at codon 541 in the NHLBI Exome Sequencing Project (ESP), which currently includes over 4200 Caucasian and over 2200 African American individuals (as of December 29, 2012). The phenotype of individuals in ESP is not publicly available, however the cohorts that were merged to create this dataset were all either general population samples or samples recruited for common cardiovascular disease such as hypertension. Rudenskaya et al. (2008) did not find the variant in 100 controls, Van Tintelen et al. (2007) did not find variation at codon 541 in 150 controls, Forissier et al. (2003) did not find variation in 100 controls, nor Hookana et al, (2008) in 96 controls. Vytopil et al. (2003) did not report controls.