rs267607578
Variant summary
Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong
The NM_170707.4(LMNA):c.1412G>A(p.Arg471His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,614,020 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. R471C) has been classified as Likely pathogenic.
Frequency
Consequence
NM_170707.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 19 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LMNA | NM_170707.4 | c.1412G>A | p.Arg471His | missense_variant | 8/12 | ENST00000368300.9 | |
LMNA | NM_005572.4 | c.1412G>A | p.Arg471His | missense_variant | 8/10 | ENST00000677389.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LMNA | ENST00000368300.9 | c.1412G>A | p.Arg471His | missense_variant | 8/12 | 1 | NM_170707.4 | P1 | |
LMNA | ENST00000677389.1 | c.1412G>A | p.Arg471His | missense_variant | 8/10 | NM_005572.4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152182Hom.: 0 Cov.: 32
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461838Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 727224
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152182Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74342
ClinVar
Submissions by phenotype
not provided Pathogenic:5Other:1
Likely pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
not provided, no classification provided | literature only | Epithelial Biology; Institute of Medical Biology, Singapore | - | - - |
Likely pathogenic, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | May 31, 2017 | 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 09, 2023 | 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) - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jun 11, 2019 | - - |
Dilated cardiomyopathy 1A Pathogenic:4
Likely pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Sep 09, 2021 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Jul 09, 2015 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | 3billion | Feb 23, 2023 | 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. - |
Pathogenic, criteria provided, single submitter | not provided | Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin | - | - - |
Primary dilated cardiomyopathy Pathogenic:4
Likely pathogenic, no assertion criteria provided | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 20, 2015 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Blueprint Genetics | Aug 21, 2015 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Oct 02, 2023 | This missense variant replaces arginine with histidine at codon 471 in the lamin tail domain of the LMNA protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). An experimental functional study using transfected COS7 cells has shown that this variant does not cause abnormal lamin A localization or morphology compared to wild-type (PMID: 20160190). Another experimental functional study using fibroblasts derived from heterozygous carrier individuals has shown that this variant causes increased lamin C isoform levels compared to lamin A isoform levels (PMID: 29943882). The clinical relevance of this observation is not known. This variant has been reported in individuals affected with dilated cardiomyopathy (PMID: 18585512, 24503780, 25569433, 29095976, 29943882, 31983221, 35026164). It has been shown that this variant segregates with disease in multiple affected individuals in one family (PMID: 29943882). This variant has also been reported in an individual affected with sudden unexplained death and suspected to be affected with dilated cardiomyopathy (PMID: 22177269). Additionally, this variant has been reported in individuals affected with laminopathy (PMID: 18646565, 28663758). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Apr 28, 2011 | 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. - |
Charcot-Marie-Tooth disease type 2 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 06, 2024 | 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. - |
Cardiovascular phenotype Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 13, 2023 | 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at