Submissions for variant NM_170707.4(LMNA):c.568C>T (p.Arg190Trp)

gnomAD frequency: 0.00001  dbSNP: rs59026483

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000057419	SCV000229074	pathogenic	not provided	2015-05-05	criteria provided, single submitter	clinical testing
GeneDx	RCV000057419	SCV000234674	pathogenic	not provided	2023-12-01	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate a damaging effect as this variant results in significant alterations in the secondary and tertiary structure of the protein, perturbing the protein's intrinsic self-association behavior (PMID: 24386194, 23701190); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20307303, 33336002, 30420677, 31311496, 31317183, 23701190, 20413395, 16061563, 25988045, 17729299, 22199124, 26899768, 26199943, 23328570, 16537768, 15219508, 23349452, 15539782, 17334235, 28416588, 28679633, 29253866, 31028937, 31383942, 31983221, 31402444, 30078822, 36396199, 32880476, 32041989, 30847666, 36136372, 37624850, 36550158, 34975533, 29878125, 36120560, 10939567, 24386194, 11897440)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000535082	SCV000657816	pathogenic	Charcot-Marie-Tooth disease type 2	2024-01-03	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 190 of the LMNA protein (p.Arg190Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 11897440, 15219508, 16061563, 16537768, 22199124, 26199943). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 66908). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects LMNA function (PMID: 23701190, 24386194). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000619878	SCV000737299	pathogenic	Cardiovascular phenotype	2024-08-21	criteria provided, single submitter	clinical testing	The c.568C>T (p.R190W) alteration is located in exon 3 (coding exon 3) of the LMNA gene. This alteration results from a C to T substitution at nucleotide position 568, causing the arginine (R) at amino acid position 190 to be replaced by a tryptophan (W). Based on data from gnomAD, the T allele has an overall frequency of 0.001% (1/152196) total alleles studied. The highest observed frequency was 0.110% (1/912) of Amish alleles. This alteration has been reported in a number of individuals with dilated cardiomyopathy including one reported de novo case, and segregation studies have identified a strong disease association (Arbustini, 2002; Hermida-Prieto, 2004; Sylvius, 2005; Kärkkäinen, 2006; Song, 2007; Vaikhanskaya, 2014; Cuenca, 2016). This amino acid position is highly conserved in available vertebrate species. In vitro studies have suggested that this alteration would alter protein structure and self-association behavior (Banerjee, 2013; Bhattacharjee, 2013). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000057419	SCV000885657	pathogenic	not provided	2017-12-27	criteria provided, single submitter	clinical testing	The LMNA c.568C>T; p.Arg190Trp variant (rs59026483) has been reported in several individuals with dilated cardiomyopathy and shown to segregate with disease in multiple families (Arbustini 2002, Hermida-Prieto 2003, Karkkainen 2006, Pethig 2005, Song 2007, Sylvius 2005, Quarta 2012, see UMD-LMNA database). In addition, functional studies show the variant protein has altered viscoelastic properties, degrades more rapidly, and forms more protein aggregates compared to wild type protein (Banerjee 2013, Bhattacharjee 2013). This variant is reported as pathogenic in ClinVar (Variation ID: 66908), and is absent from the general population databases (1000 Genomes Project, Exome Variant Server, Genome Aggregation Database) indicating it is not a common polymorphism. The arginine at codon 190 is highly conserved and computational algorithms (SIFT, PolyPhen2, MutationTaster) predict this variant to be damaging to the protein. Based on the above information, the p.Arg190Trp variant is considered pathogenic. REFERENCES Link to UMD-LMNA database: http://www.umd.be/LMNA/ Arbustini E et al. Autosomal dominant dilated cardiomyopathy with atrioventricular block: a lamin A/C defect-related disease. J Am Coll Cardiol. 2002 Mar 20;39(6):981-90. Banerjee A et al. Viscoelastic behavior of human lamin A proteins in the context of dilated cardiomyopathy. PLoS One. 2013 Dec 30;8(12):e83410. Bhattacharjee P et al. Structural alterations of Lamin A protein in dilated cardiomyopathy. Biochemistry. 2013 Jun 18;52(24):4229-41. Hermida-Prieto M et al. Familial dilated cardiomyopathy and isolated left ventricular noncompaction associated with lamin A/C gene mutations. Am J Cardiol. 2004 Jul 1;94(1):50-4. Karkkainen S et al. Novel mutations in the lamin A/C gene in heart transplant recipients with end stage dilated cardiomyopathy. Heart. 2006 Apr;92(4):524-6. Pethig K et al. LMNA mutations in cardiac transplant recipients. Cardiology. 2005;103(2):57-62. Song K et al. Lamin A/C mutations associated with familial and sporadic cases of dilated cardiomyopathy in Koreans. Exp Mol Med. 2007 Feb 28;39(1):114-20.
CeGaT Center for Human Genetics Tuebingen	RCV000057419	SCV003916511	pathogenic	not provided	2023-11-01	criteria provided, single submitter	clinical testing	LMNA: PM2, PM5, PP1:Moderate, PS4:Moderate, PP3, PS3:Supporting
PreventionGenetics, part of Exact Sciences	RCV004528262	SCV004106788	pathogenic	LMNA-related disorder	2023-05-27	criteria provided, single submitter	clinical testing	The LMNA c.568C>T variant is predicted to result in the amino acid substitution p.Arg190Trp. This variant has been reported in many individuals with dilated cardiomyopathy (Arbustini et al. 2002. PubMed ID: 11897440; Quarta et al. 2011. PubMed ID: 22199124; See Supp. Table 1 in Dal Ferro et al. 2017. PubMed ID: 28416588; See Dataset S5 in Ito et al. 2017. PubMed ID: 28679633). Functional studies indicate this variant alters protein structure and disrupts self-association of the lamin A protein (Bhattacharjee et al. 2013. PubMed ID: 23701190). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant has been reported in ClinVar by many outside laboratories as pathogenic (www.ncbi.nlm.nih.gov/clinvar/variation/66908). This variant is interpreted as pathogenic.
All of Us Research Program, National Institutes of Health	RCV003996512	SCV004845015	pathogenic	Primary dilated cardiomyopathy	2024-01-12	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with tryptophan at codon 190 of the intermediate filament rod domain of the lamin A/C proteins. 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 have shown that this variant may disrupt the viscoelasticity of lamin A in the nuclear envelope (PMID: 23701190, 24386194). This variant has been reported in more than 10 unrelated individuals affected with dilated cardiomyopathy (PMID: 11897440, 15219508, 15539782, 16061563, 16537768, 17334235, 29947763, 23349452, 26199943, 26899768, 29947763, 32041989, 32880476; DOI 10.3390 Cuesta-Llavona 2022). It has also been reported in an individual affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 22199124). It has been shown that this variant segregates with disease in multiple affected individuals across multiple families (PMID: 11897440, 15219508, 15539782, 16061563, 17334235, 29947763, 26199943). A different variant occurring at the same codon, p.Arg190Gln, is a well documented pathogenic mutation (Clinvar variation ID: 66910), indicating that arginine at this position is important for LMNA protein function. 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.
Epithelial Biology; Institute of Medical Biology, Singapore	RCV000057419	SCV000088533	not provided	not provided		no assertion provided	not provided
Institut für Laboratoriums- und Transfusionsmedizin, Herz- und Diabeteszentrum Nordrhein-Westfalen	RCV000491585	SCV000298111	pathogenic	Dilated cardiomyopathy 1S	2016-05-01	no assertion criteria provided	clinical testing
Gharavi Laboratory, Columbia University	RCV000057419	SCV000809471	pathogenic	not provided	2018-09-16	no assertion criteria provided	research
Clinical Genetics, Academic Medical Center	RCV000057419	SCV001925111	pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000057419	SCV001929734	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000057419	SCV001951920	pathogenic	not provided		no assertion criteria provided	clinical testing