ClinVar Miner

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

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Total submissions: 7
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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
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000057273 SCV000335899 pathogenic not provided 2018-01-31 criteria provided, single submitter clinical testing
Epithelial Biology; Institute of Medical Biology, Singapore RCV000057273 SCV000088386 not provided not provided no assertion provided not provided
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.
Genetic Services Laboratory, University of Chicago RCV000500734 SCV000595631 pathogenic Muscular dystrophy 2013-02-08 criteria provided, single submitter clinical testing
Invitae RCV000472112 SCV000548859 pathogenic Charcot-Marie-Tooth disease, type 2 2018-11-07 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.
OMIM RCV000015565 SCV000035830 pathogenic Benign scapuloperoneal muscular dystrophy with cardiomyopathy 1999-03-01 no assertion criteria provided literature only

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