Submissions for variant NM_170707.4(LMNA):c.1412G>A (p.Arg471His)

gnomAD frequency: 0.00001  dbSNP: rs267607578

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000030148	SCV000065009	likely pathogenic	Primary dilated cardiomyopathy	2011-04-28	criteria provided, single submitter	clinical testing	The Arg471His variant has been reported in one individual with DCM and was absen t from 300 Caucasian control chromosomes, supporting a pathogenic role (Parks 20 08). Our laboratory has previously identified this variant in two affected indiv iduals (one with DCM, conduction system disease and skeletal myopathy and one wi th ventricular tachycardia) and was absent from 412 Caucasian and 354 Black cont rol chromosomes (LMM unpublished data). Furthermore, arginine (Arg) at amino aci d position 471 is conserved in evolutionarily distant species, suggesting that a change would not be tolerated. Finally, variants in LMNA have been identified i n a range of disorders including dilated cardiomyopathy with or without conducti on system disease, which is consistent with the features observed with this vari ant thus far. In summary, the data available so far suggests that the Arg471His variant is likely to be pathogenic.
GeneDx	RCV000057294	SCV000234701	pathogenic	not provided	2023-06-09	criteria provided, single submitter	clinical testing	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: 20160190, 24846508, 29095976, 27532257, 33019804, 22177269, 24375749, 24623722, 22337857, 25569433, 22464770, 18585512, 18646565, 28663758, 29943882, 31729605, 31383942, 31983221, 24503780, 23582089, 30078822, 33906374, 23054336, 34862408, 10939567)
Athena Diagnostics Inc	RCV000154177	SCV000255782	likely pathogenic	Dilated cardiomyopathy 1A	2015-07-09	criteria provided, single submitter	clinical testing
Blueprint Genetics	RCV000030148	SCV000264012	likely pathogenic	Primary dilated cardiomyopathy	2015-08-21	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000057294	SCV000604109	likely pathogenic	not provided	2017-05-31	criteria provided, single submitter	clinical testing	The p.Arg471His variant (rs267607578) is absent from general population databases such as 1000 Genomes, the NHLBI GO Exome Sequencing Project (ESP), and the Genome Aggregation Database (gnomAD) browser, and has been observed in multiple cohorts of dilated cardiomyopathy (DCM)/muscular dystrophy patients (Astejada 2007, Larsen 2012, Parks 2008, Pugh 2014, van Rijsingen 2013, Walsh 2017). It is also classified in the ClinVar database as likely pathogenic by multiple clinical laboratories (Variation ID: 36476). While observed in several symptomatic individuals (and multiple pedigrees suggestive of dominantly inherited disease), this variant has not been shown to segregate with disease. Additionally, functional assays of p.Arg471His variant protein have yielded mixed results: overexpression of p.Arg471His in COS7 cells did not alter nuclear envelope architecture, as did the overexpression of other purportedly pathogenic LMNA variants (Cowan 2010). However, another assay examining the effect of pathogenic LMNA variants interactions between LMNA and various binding partners suggests that p.Arg471His disrupts approximately 12% of such interactions, whereas other more benign-learning variants disrupt fewer (Dittmer 2014). The arginine at codon 471 is highly conserved considering 12 species up to fruitfly (Alamut software v2.9), and computational analyses suggest this variant has a significant effect on LMNA protein structure/function (SIFT: damaging, PolyPhen2: probably damaging, and Mutation Taster: disease causing). Therefore, based on the available information, the p.Arg471His variant is likely to be pathogenic.
Ambry Genetics	RCV000621248	SCV000735316	pathogenic	Cardiovascular phenotype	2023-03-13	criteria provided, single submitter	clinical testing	The p.R471H pathogenic mutation (also known as c.1412G>A), located in coding exon 8 of the LMNA gene, results from a G to A substitution at nucleotide position 1412. The arginine at codon 471 is replaced by histidine, an amino acid with highly similar properties. This alteration has been reported in individuals with laminopathy and dilated cardiomyopathy (DCM), including some with conduction system disease (Astejada MN et al. Acta Myol. 2007; 26(3):159-64; Parks SB et al. Am Heart J. 2008;156(1):161-9; Larsen MK et al. Forensic Sci Int 2012;219(1-3):33-8; Miller EM et al. J Genet Couns. 2012;22(2):258-67; Pugh TJ et al. Genet Med 2014;16(8):601-8). In one family, this mutation was detected in a proband with DCM and co-segregated with disease in similarly affected family members across multiple generations (Al-Saaidi RA et al. Eur. J. Heart Fail., 2018 10;20:1404-1412). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on internal structural analysis, this variant lies in a structured domain and is predicted to be moderately disruptive (Magracheva E et al. Acta Crystallogr Sect F Struct Biol Cryst. 2009;65(Pt 7):665-70). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Invitae	RCV000653872	SCV000775762	pathogenic	Charcot-Marie-Tooth disease type 2	2024-01-06	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 471 of the LMNA protein (p.Arg471His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant dilated cardiomyopathy and limb-girdle muscular dystrophy (PMID: 18646565, 22177269, 23582089, 27532257, 29943882). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 36476). 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 are conflicting or provide insufficient evidence to determine the effect of this variant on LMNA function (PMID: 20160190). For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity	RCV000057294	SCV002022702	likely pathogenic	not provided	2019-06-11	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV000154177	SCV002581616	likely pathogenic	Dilated cardiomyopathy 1A	2021-09-09	criteria provided, single submitter	clinical testing
3billion	RCV000154177	SCV003841481	pathogenic	Dilated cardiomyopathy 1A	2023-02-23	criteria provided, single submitter	clinical testing	The variant is not observed in the gnomAD v2.1.1 dataset. Missense variant. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.90; 3Cnet: 0.85). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000036476). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 18585512, 22177269, 23582089, 27532257, 29095976, 29943882). The variant has been reported to co-segregate with the disease in at least 7 similarly affected relatives/individuals in at least two unrelated families (PMID: 29943882). Different missense changes at the same codon (p.Arg471Cys, p.Arg471Gly) have been reported to be associated with LMNA-related disorder (ClinVar ID: VCV000014503 / PMID: 12768443, 18041775 / 3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin	RCV000154177	SCV004037142	pathogenic	Dilated cardiomyopathy 1A		criteria provided, single submitter	not provided
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000030148	SCV000052803	likely pathogenic	Primary dilated cardiomyopathy	2015-05-20	no assertion criteria provided	clinical testing
Epithelial Biology; Institute of Medical Biology, Singapore	RCV000057294	SCV000088407	not provided	not provided		no assertion provided	not provided
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000057294	SCV001797616	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000057294	SCV001963533	likely pathogenic	not provided		no assertion criteria provided	clinical testing