rs59026483

Positions:

• chr1-156134457-C-T

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5_Very_Strong

The NM_170707.4(LMNA):​c.568C>T​(p.Arg190Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,196 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R190Q) has been classified as Likely pathogenic.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: LMNA NM_170707.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:13 O:1
• Conservation: PhyloP100: 2.32

Genes affected

LMNA (HGNC:6636): (lamin A/C) The protein encoded by this gene is part of the nuclear lamina, a two-dimensional matrix of proteins located next to the inner nuclear membrane. The lamin family of proteins make up the matrix and are highly conserved in evolution. During mitosis, the lamina matrix is reversibly disassembled as the lamin proteins are phosphorylated. Lamin proteins are thought to be involved in nuclear stability, chromatin structure and gene expression. Vertebrate lamins consist of two types, A and B. Alternative splicing results in multiple transcript variants. Mutations in this gene lead to several diseases: Emery-Dreifuss muscular dystrophy, familial partial lipodystrophy, limb girdle muscular dystrophy, dilated cardiomyopathy, Charcot-Marie-Tooth disease, and Hutchinson-Gilford progeria syndrome. [provided by RefSeq, May 2022]

LMNA (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 17 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 8 uncertain in NM_170707.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-156134458-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 66910.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), LMNA. . Gene score misZ 2.3673 (greater than the threshold 3.09). Trascript score misZ 3.0905 (greater than threshold 3.09). GenCC has associacion of gene with familial partial lipodystrophy, Dunnigan type, autosomal recessive Emery-Dreifuss muscular dystrophy, LMNA-related cardiocutaneous progeria syndrome, atrioventricular block, dilated cardiomyopathy 1A, Emery-Dreifuss muscular dystrophy 2, autosomal dominant, atypical Werner syndrome, restrictive dermopathy 1, autosomal semi-dominant severe lipodystrophic laminopathy, Emery-Dreifuss muscular dystrophy 3, autosomal recessive, dilated cardiomyopathy, Charcot-Marie-Tooth disease type 2B1, dilated cardiomyopathy-hypergonadotropic hypogonadism syndrome, arrhythmogenic right ventricular cardiomyopathy, familial isolated dilated cardiomyopathy, mandibuloacral dysplasia with type A lipodystrophy, autosomal dominant Emery-Dreifuss muscular dystrophy, heart-hand syndrome, Slovenian type, congenital muscular dystrophy due to LMNA mutation, lethal restrictive dermopathy, Hutchinson-Gilford progeria syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.933
• PP5: Variant 1-156134457-C-T is Pathogenic according to our data. Variant chr1-156134457-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 66908.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-156134457-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LMNA	NM_170707.4	c.568C>T	p.Arg190Trp	missense_variant	3/12	ENST00000368300.9	NP_733821.1
LMNA	NM_005572.4	c.568C>T	p.Arg190Trp	missense_variant	3/10	ENST00000677389.1	NP_005563.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LMNA	ENST00000368300.9	c.568C>T	p.Arg190Trp	missense_variant	3/12	1	NM_170707.4	ENSP00000357283.4
LMNA	ENST00000677389.1	c.568C>T	p.Arg190Trp	missense_variant	3/10		NM_005572.4	ENSP00000503633.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152196 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 33

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152196 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74352

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000151

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:13 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:8 Other:1

Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
not provided, no classification provided	literature only	Epithelial Biology; Institute of Medical Biology, Singapore	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 01, 2023	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) -
Pathogenic, no assertion criteria provided	research	Gharavi Laboratory, Columbia University	Sep 16, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Dec 27, 2017	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 05, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	LMNA: PM2, PM5, PP1:Moderate, PS4:Moderate, PP3, PS3:Supporting -

Dilated cardiomyopathy 1S Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Institut für Laboratoriums- und Transfusionsmedizin, Herz- und Diabeteszentrum Nordrhein-Westfalen

May 01, 2016

- -

Charcot-Marie-Tooth disease type 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 03, 2024

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. -

LMNA-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 27, 2023

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. -

Primary dilated cardiomyopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Jan 12, 2024

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. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 21, 2024

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
CardioboostCm	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	.;.;.;D;.;.;.;D;.
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.65	D
MetaRNN	Pathogenic	0.93	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Pathogenic	3.7	H;.;H;H;H;.;.;.;.
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-7.2	D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.85
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D;D
Polyphen		1.0	D;.;D;D;.;.;D;.;.
Vest4		0.91
MutPred		0.80		Loss of disorder (P = 0.0043);Loss of disorder (P = 0.0043);Loss of disorder (P = 0.0043);Loss of disorder (P = 0.0043);Loss of disorder (P = 0.0043);.;.;.;.;
MVP		0.98
MPC		2.1
ClinPred		0.99	D
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		3.2
Varity_R		0.92
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs59026483; hg19: chr1-156104248;