1-156136094-G-T

Position:

• chr1-156136094-G-T

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_170707.4(LMNA):​c.1130G>T​(p.Arg377Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,732 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R377C) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: LMNA NM_170707.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9 O:1
• Conservation: PhyloP100: 8.12

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 19 ACMG points.

• PM1: In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 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 chr1-156136093-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 48031.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, 0.972
• PP5: Variant 1-156136094-G-T is Pathogenic according to our data. Variant chr1-156136094-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 66778.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-156136094-G-T is described in Lovd as [Pathogenic]. Variant chr1-156136094-G-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LMNA	NM_170707.4	c.1130G>T	p.Arg377Leu	missense_variant	6/12	ENST00000368300.9	NP_733821.1
LMNA	NM_005572.4	c.1130G>T	p.Arg377Leu	missense_variant	6/10	ENST00000677389.1	NP_005563.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LMNA	ENST00000368300.9	c.1130G>T	p.Arg377Leu	missense_variant	6/12	1	NM_170707.4	ENSP00000357283.4
LMNA	ENST00000677389.1	c.1130G>T	p.Arg377Leu	missense_variant	6/10		NM_005572.4	ENSP00000503633.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461732 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 727174

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4 Other:1

not provided, no classification provided	literature only	Epithelial Biology; Institute of Medical Biology, Singapore	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Primary dilated cardiomyopathy Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Aug 15, 2023	This missense variant replaces arginine with leucine at codon 377 of the intermediate filament rod domain of the lamin A/C protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in multiple individuals affected with dilated cardiomyopathy (PMID: 12649505, 18035086, 18926329, 23349452, 32880476). This variant has also been reported in individuals affected with a range of laminopathy phenotypes, including atrial fibrillation (PMID: 35449878), Emery-Dreifuss muscular dystrophy (PMID: 12649505), limb-girdle muscular dystrophy (PMID: 15832002), and muscle weakness (PMID: 32528171). Different variants affecting the same codon, p.Arg377Cys and p.Arg377His, are considered to be disease-causing for dilated cardiomyopathy (Clinvar variation ID: 14495 and 48031), 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 Likely Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 12, 2023	The p.Arg377Leu variant in LMNA has been reported in at least 7 individuals with dilated cardiomyopathy (DCM), 3 of whom had additional features of muscular dystrophy (Ki 2002 PMID: 12032588, Boriani 2003 PMID: 12649505, van Tintelen 2007 PMID: 18035086, van Lint 2019 PMID: 30847666,Verdonschot 2020 PMID: 32880476, Stiekema 2021 PMID: 34638534, LMM data), and segregated with DCM in 2 relatives from 1 family (van Tintelen 2007 PMID: 18035086). In addition, this variant has been identified in 2 individuals with unspecified cardiomyopathy, 1 of whom also had conduction disease (te Rijdt 2017 PMID: 28759816, LMM data) as well as in at least 2 individuals with clinical features of myopathy/muscular dystrophy one of whom also had features of a conduction disorder (Madej-Pilarczyk 2018 PMID: 28987496, van Lint 2019 PMID: 30847666). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 66778) and was absent from large population studies. In vitro functional studies show abnormalities in lamin localization, supporting an impact on protein function (Stiekema 2021 PMID: 34638534, Anderson 2021 PMID: 34862408) and computational prediction tools and conservation analysis suggest that the p.Arg377Leu variant may impact the protein. Furthermore, two different substitutions at this location (p.Arg377His and p.Arg377Cys) have been reported in multiple patients with DCM and LMNA-associated muscular dystrophies (Muchir 2000 PMID: 10814726, Sebillon 2003 PMID: 12920062, Perrot 2006 PMID: 16386954, Meune 2006 PMID: 16407522, Astejada 2007 PMID: 18646565, Lashevsky 2008, Deconinck 2010 PMID: 20576434, Komaki 2011 PMID: 21632249, Sylvius 2011 PMID: 21840938, van Rijsingen 2013 PMID: 23183350, Pugh 2014 PMID: 24503780), 1 least one of which (p.Arg377His) been classified as pathogenic by multiple laboratories, suggesting that a change at this position may not be tolerated. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant DCM. ACMG/AMP Criteria applied: PM2_Supporting, PS4_Moderate, PP3, PS3_Supporting, PM5. -

Charcot-Marie-Tooth disease type 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 22, 2024

This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 377 of the LMNA protein (p.Arg377Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant LMNA-related disease (PMID: 12032588, 15678000, 18035086, 18926329, 23349452, 23360689). ClinVar contains an entry for this variant (Variation ID: 66778). 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%. This variant disrupts the p.Arg377 amino acid residue in LMNA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10814726, 18646565, 21632249, 21840938, 23183350, 24503780). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Congenital muscular dystrophy due to LMNA mutation Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Neuberg Centre For Genomic Medicine, NCGM

Feb 14, 2023

The missense c.1130G>T (p.Arg377Leu) variant in LMNA gene has been reported previously in heterozygous state in multiple individuals affected with LMNA-related muscular dystrophy (van Tintelen et al. 2007; Chen et al. 2013; Madej-Pilarczyk et al. 2018). The p.Arg377Leu variant is novel (not in any individuals) in both gnomAD Exomes and 1000 Genomes databases. This variant has been reported to the ClinVar database as Uncertain Significance / Pathogenic (multiple submissions). The amino acid change p.Arg377Leu in LMNA is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Arg at position 377 is changed to a Leu changing protein sequence and it might alter its composition and physico-chemical properties. Another missense variant [p.Arg377Cys] at this residue has previously been reported to affect protein function or expression (Sylvius et al. 2011). For these reasons, this variant has been classified as Pathogenic. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 10, 2021

The p.R377L variant (also known as c.1130G>T), located in coding exon 6 of the LMNA gene, results from a G to T substitution at nucleotide position 1130. The arginine at codon 377 is replaced by leucine, an amino acid with dissimilar properties. This alteration has been detected in subjects with dilated cardiomyopathy (DCM), as well as in subjects with varying forms of muscular dystrophy, and has been reported to segregate with disease (Ki CS et al. J. Hum. Genet., 2002;47:225-8; Boriani G et al. Stroke, 2003 Apr;34:901-8; Rudnik-Schöneborn S et al. Neurogenetics, 2007 Apr;8:137-42; Verdonschot JAJ et al. Circ Genom Precis Med, 2020 10;13:476-487). Immunofluorescence studies in patient fibroblasts demonstrated nuclear abnormalities in lamin (Stiekema M et al. Int J Mol Sci, 2021 Sep;22:[Epub ahead of print]). In addition, other alterations affecting the same amino acid, p.R377C (c.1129C>T) and p.R377H (c.1130G>A), have been reported in individuals with DCM and other laminopathies, and the p.R377H variant has shown significant co-segregation in affected relatives from multiple families (Muchir A et al. Hum. Mol. Genet., 2000 May;9:1453-9; Charniot JC et al. Hum. Mutat., 2003 May;21:473-81; Sébillon P et al. J. Med. Genet., 2003 Aug;40:560-7; Perrot A et al. Eur. J. Heart Fail., 2006 Aug;8:484-93; Astejada MN et al. Acta Myol, 2007 Dec;26:159-64). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
CardioboostCm	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	.;.;.;D;.;.;.;.;D
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.77	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.7	H;.;H;H;H;.;.;.;.
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-6.9	D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D;D;D;D
Polyphen		1.0	D;.;D;D;.;.;D;.;.
Vest4		0.96
MutPred		0.84		Gain of helix (P = 0.2059);Gain of helix (P = 0.2059);Gain of helix (P = 0.2059);Gain of helix (P = 0.2059);Gain of helix (P = 0.2059);.;.;.;.;
MVP		0.99
MPC		2.3
ClinPred		1.0	D
GERP RS		5.3
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.8
Varity_R		0.95
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs61672878; hg19: chr1-156105885;