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

dbSNP: rs28933093

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
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).
CeGaT Center for Human Genetics Tuebingen	RCV000057409	SCV000574794	likely pathogenic	not provided	2016-11-01	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000015598	SCV000595617	pathogenic	Dilated cardiomyopathy 1A	2013-02-08	criteria provided, single submitter	clinical testing
Invitae	RCV000687241	SCV000814798	pathogenic	Charcot-Marie-Tooth disease type 2	2023-09-15	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects LMNA function (PMID: 23701190, 24386194, 29432544). 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. ClinVar contains an entry for this variant (Variation ID: 14504). This missense change has been observed in individual(s) with dilated cardiomyopathy (DCM) (PMID: 12920062, 18795223, 19318026, 27532257, 29432544). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 161 of the LMNA protein (p.Glu161Lys).
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001170451	SCV001333031	pathogenic	Cardiomyopathy	2021-04-30	criteria provided, single submitter	clinical testing
Dept of Medical Biology, Uskudar University	RCV003318333	SCV004021951	pathogenic	Long QT syndrome	2024-01-08	criteria provided, single submitter	research	Criteria: PS4_Strong, PS3_Supporting, PM1, PM2, PP3
All of Us Research Program, National Institutes of Health	RCV000211788	SCV004822972	pathogenic	Primary dilated cardiomyopathy	2023-04-10	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 161 in the intermediate filament rod domain of the LMNA protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies in mouse embryonic stem cells have shown that this variant causes increased nuclear blebbing and decreased nuclear lamin organization; additional functional studies have shown that this variant causes changes in the secondary and tertiary structure of the LMNA protein as well as abnormal gene expression profiles (PMID: 21179469, 23701190, 32083564, 35887646). This variant has been reported in individuals affected with dilated cardiomyopathy (PMID: 12920062, 17334235, 18795223, 18926329, 19318026, 21179469, 27532257, 34768595, 35887646, 35887646). It has been shown that this variant segregates with disease in multiple affected individuals across two families (PMID: 18926329, 35887646). 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 Pathogenic.
Ambry Genetics	RCV004018635	SCV005030794	pathogenic	Cardiovascular phenotype	2023-12-19	criteria provided, single submitter	clinical testing	The p.E161K pathogenic mutation (also known as c.481G>A), located in coding exon 2 of the LMNA gene, results from a G to A substitution at nucleotide position 481. The glutamic acid at codon 161 is replaced by lysine, an amino acid with similar properties. This alteration has been reported in probands with a history of LMNA-related disease (Pasotti M et al. J Am Coll Cardiol, 2008 Oct;52:1250-60; Perrot A et al. Basic Res Cardiol, 2009 Jan;104:90-9; Walsh R et al. Genet Med, 2017 Feb;19:192-203; Gigli M et al. J Am Coll Cardiol, 2019 Sep;74:1480-1490; Ferradini V et al. J Clin Med, 2021 Oct;10:; Ambry internal data). In addition, studies show this variant has an impact on protein function (Bhattacharjee P et al. Biochemistry, 2013 Jun;52:4229-41; Laurini E et al. Cardiovasc Res, 2018 May;114:846-857). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. 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.
OMIM	RCV000015598	SCV000035863	pathogenic	Dilated cardiomyopathy 1A	2003-08-01	no assertion criteria provided	literature only
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000211788	SCV000065044	pathogenic	Primary dilated cardiomyopathy	2009-06-26	no assertion criteria provided	clinical testing
Epithelial Biology; Institute of Medical Biology, Singapore	RCV000057409	SCV000088522	not provided	not provided		no assertion provided	not provided
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.
Sangiuolo Lab - Medical Genetics Laboratory, Tor Vergata University	RCV000015598	SCV001593103	pathogenic	Dilated cardiomyopathy 1A	2021-04-27	no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000057409	SCV001743140	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000057409	SCV001952305	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000057409	SCV001964197	pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000057409	SCV002033947	pathogenic	not provided		no assertion criteria provided	clinical testing