ClinVar Miner

Submissions for variant NM_170707.4(LMNA):c.1357C>T (p.Arg453Trp) (rs58932704)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Center for Genetic Medicine Research,Children's National Medical Center RCV000230383 SCV000265777 likely pathogenic Limb-girdle muscular dystrophy, type 1B 2015-12-01 criteria provided, single submitter research
GeneDx RCV000057273 SCV000292719 pathogenic not provided 2018-12-21 criteria provided, single submitter clinical testing The R453W pathogenic variant in the LMNA gene has been reported multiple times in association with various types of muscular dystrophy. This variant was initially reported in a family with autosomal dominant Emery-Dreifuss muscular dystrophy (Bonne et al., 1999). The R453W variant has also been reported in children with limb-girdle muscular dystrophy 1B and congenital fiber type disproportion myopathy (Mitsuhashi et al., 2010; Kajino et al., 2013). Functional studies have demonstrated that cells expressing the R453W variant have structural abnormalities as well as anomalous differentiation and proliferation (Favreau et al., 2004; Emerson et al., 2009; Folker et al 2011). The R453W variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R453W variant is a non-conservative change at a conserved residue. We interpret R453W as a pathogenic variant.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000057273 SCV000335899 pathogenic not provided 2018-01-31 criteria provided, single submitter clinical testing
Invitae RCV000472112 SCV000548859 pathogenic Charcot-Marie-Tooth disease, type 2 2019-12-16 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 453 of the LMNA protein (p.Arg453Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is not present in population databases (rs58932704, ExAC no frequency). This variant has been reported in individuals affected with autosomal dominant Emery-Dreifuss muscular dystrophy, limb-girdle muscular dystrophy type 1B and congenital fiber-type disproportion (PMID: 18396274, 22326558, 20980393, 24642510). Experimental studies have shown that this missense change impairs multiple aspects of LMNA protein function (PMID: 21173262, 14749366, 1839274). A different missense substitution at this codon (p.Arg453Pro) has been determined to be pathogenic (PMID: 18551515). This suggests that the arginine residue is critical for LMNA protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
Genetic Services Laboratory,University of Chicago RCV000500734 SCV000595631 pathogenic Muscular dystrophy 2013-02-08 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001095717 SCV001251555 likely pathogenic Dilated cardiomyopathy 1A 2020-02-19 criteria provided, single submitter clinical testing The LMNA c.1357C>T (p.Arg453Trp) variant is a missense variant. A literature search was performed for the gene, cDNA change, and amino acid change. No publications reporting this variant in association with isolated dilated cardiomyopathy were found based on this search. However, multiple publications report the variant in association with various types of muscular dystrophy with cardiac manifestations (Bonne et al. 1999; Astejada et al. 2007; Dai et al. 2015; Lee et al. 2017). The variant is not found in the Genome Aggregation Database in a region of good sequencing coverage, which suggests the variant is rare. Functional studies in mouse myoblast C2C12 cells expressing the p.Arg453Trp variant showed poor cell differentiation, improper cell cycle exit, and excessive committment to apoptosis (Favreau et al. 2004). The Arg453 residue lies within the laminin tail domain, a region that may be involved in protein or DNA binding, and in silico analyses suggest the variant is deleterious. Based on the evidence and the application of the ACMG criteria, the p.Arg453Trp variant is classified as likely pathogenic for dilated cardiomyopathy.
Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn RCV000015565 SCV001251976 pathogenic Emery-Dreifuss muscular dystrophy 2, autosomal dominant criteria provided, single submitter clinical testing The presence of a disease-causing variant was detected in exon 7 of the LMNA gene. The name of the variant is: NM_170707:c.1357C> T;p.Arg453Trp. In the parents, this variant could not be detected in 21 reads each, which is why it is very likely that the patient developed it anew (de novo). This variant is not listed in population-based databases (gnomAD, ExAC, EVS and 1000Genomes). In dbSNP it is listed under the rs number rs58932704 . In the phanotype-related databases LOVD, HGMD and ClinVar the variant is already listed several times and is generally considered to be mainly pathogenic, but also probably pathogenic. The mutation prediction programs MutationTaster, SIFT, PROVEAN and PolyPhen-2 assess the variant as pathogenic, the CADD score is 34. In order to assess the possible disturbance of splice behavior by the above-mentioned variant, we have used various programs for the prediction of splice sites and splice enhancers with the aid of the Alamut software. The in-silica analysis does not provide any significant indication of a change in splice1 behavior. Functional studies have shown significant effects of this variant on protein function (e.g. PMID 21173262, 14749366, 20980393, 25948554). The ACMG classification for this variant is: pathogenic (class 5; PS2 PS3 PM2 PP3 PP5).
OMIM RCV000015565 SCV000035830 pathogenic Emery-Dreifuss muscular dystrophy 2, autosomal dominant 1999-03-01 no assertion criteria provided literature only
Epithelial Biology; Institute of Medical Biology, Singapore RCV000057273 SCV000088386 not provided not provided no assertion provided not provided

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