ClinVar Miner

Submissions for variant NM_170707.4(LMNA):c.1412G>A (p.Arg471His) (rs267607578)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 9
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare 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and one wi th ventricular tachycardia) and was absent from 412 Caucasian and 354 Black cont rol chromosomes (LMM unpublished data).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 2018-07-18 criteria provided, single submitter clinical testing The R471H variant in the LMNA gene has been reported in a patient with a laminopathy, as well as in individuals with familial dilated cardiomyopathy (DCM) and conduction system disease (Astejada et al., 2007; Parks et al., 2008; Cowan et al., 2010; Lakdawala et al., 2012; Norton et al., 2012; Pugh et al., 2014; Walsh et al., 2017; Hasselberg et al., 2017). Additionally, this variant was recently found in a proband with DCM and shown to segregate with disease in eight affected relatives in this family (Al-Saaidi et al., 2018). This variant has also been identified in individuals with DCM referred for genetic testing at GeneDx. The R471H variant is not observed in large population cohorts (Lek et al., 2016).The R471 residue is located in the immunoglobin fold domain, amino-terminal to the nuclear localization signal of lamin A (Muschke et al., 2007). In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Furthermore, other missense variants at the same residue (R471C, R471G) have been reported in HGMD in association with LMNA-related disorders (Cao et al., 2003; Muschke et al., 2007), supporting the functional importance of this residue. Functional studies have shown that R471H does not appear to disrupt nuclear morphology or the incorporation of mutant protein into the cytoskeleton (Cowan et al., 2010; Al-Saadi et al., 2018). However, Al-Saaidi et al. (2018) demonstrated that R471H increases the expression of lamin C protein, relative to lamin A protein, and the authors propose that this skewed lamin A/C ratio may destabilize the nuclear envelope and disrupt mechanical support of the nucleus.
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 2019-10-15 criteria provided, single submitter clinical testing In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Rarity in general population databases (dbsnp, esp, 1000 genomes);Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Good segregation with disease (lod 1.5-3 = 5-9 meioses);Structural Evidence
Invitae RCV000653872 SCV000775762 pathogenic Charcot-Marie-Tooth disease, type 2 2019-12-24 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 471 of the LMNA protein (p.Arg471His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is not present in population databases (rs267607578, ExAC no frequency). This variant has been observed to segregate with dilated cardiomyopathy (DCM) in a family (PMID: 29943882). This variant has been reported in an individual affected with limb-girdle muscular dystrophy (PMID: 18646565) and two individuals affected with DCM (PMID: 23582089, 27532257). This variant was also reported in an individual who died unexpectedly with a suspicion of DCM (PMID: 22177269). ClinVar contains an entry for this variant (Variation ID: 36476). This variant has been reported to have conflicting or insufficient data to determine the effect on LMNA protein function (PMID: 20160190). For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America 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

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.