ClinVar Miner

Submissions for variant NM_170707.4(LMNA):c.481G>A (p.Glu161Lys) (rs28933093)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CeGaT Praxis fuer Humangenetik Tuebingen RCV000057409 SCV000574794 likely pathogenic not provided 2016-11-30 criteria provided, single submitter clinical testing
Epithelial Biology; Institute of Medical Biology, Singapore RCV000057409 SCV000088522 not provided not provided no assertion provided not provided
GeneDx RCV000057409 SCV000234736 pathogenic not provided 2018-12-12 criteria provided, single submitter clinical testing The pathogenic E161K variant in the LMNA gene has been published in association with dilated cardiomyopathy (Sebillon et al., 2003; Song et al., 2007; Pasotti et al., 2008; Perrot et al., 2009; Millat et al., 2011; Pugh et al., 2014; Walsh et al., 2017). The E161K variant was described in detail by Sébillon et al. (2003) in one family with two reported cardiac deaths. Seven living family members were heterozygous for this variant, two of whom had DCM with atrial fibrillation and congestive heart failure necessitating heart transplantation, three others had only atrial fibrillation, and two younger individuals were asymptomatic (Sébillon et al., 2003). The same study reported that the E161K pathogenic variant occurs in the central alpha-helical rod domain of the lamin A/C protein, where other variants causing DCM associated with conduction disease have been reported (Sébillon et al., 2003). More recently, functional studies of E161K in mutant heart and fibroblasts showed that this variant is likely to disrupt normal gene expression due to alteration in the nuclear positioning of chromosomes (Mewborn et al., 2010; Puckelwartz et al., 2011). Additional functional studies in vitro have shown that E161K results in alteration of protein secondary and tertiary structure with improper oligomerization suggesting that this variant alters mechanotransduction in cardiomyocytes (Bhattacharjee et al., 2013; Banerjee et al., 2013). Furthermore, the E161K variant is not observed in large population cohorts (Lek et al., 2016).
Genetic Services Laboratory, University of Chicago RCV000015598 SCV000595617 pathogenic Dilated cardiomyopathy 1A 2013-02-08 criteria provided, single submitter clinical testing
GenomeConnect, ClinGen RCV000015598 SCV000986874 not provided Dilated cardiomyopathy 1A no assertion provided phenotyping only Variant interpretted as pathogenic and reported on 05/23/2012 by GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Invitae RCV000687241 SCV000814798 pathogenic Charcot-Marie-Tooth disease, type 2 2018-12-31 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 161 of the LMNA protein (p.Glu161Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in numerous affected individuals with dilated cardiomyopathy (DCM) and has been shown to segregate with DCM in several families (PMID: 27532257, 19318026, 18795223, 12920062, 29432544). ClinVar contains an entry for this variant (Variation ID: 14504). Experimental studies have shown that this missense change affects several aspects of laminin A protein function and localization (PMID: 23701190, 24386194, 29432544). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000211788 SCV000065044 pathogenic Primary dilated cardiomyopathy 2009-06-26 no assertion criteria provided clinical testing
OMIM RCV000015598 SCV000035863 pathogenic Dilated cardiomyopathy 1A 2003-08-01 no assertion criteria provided literature only

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