chr1-156136094-G-A

Position:

• chr1-156136094-G-A

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_170707.4(LMNA):​c.1130G>A​(p.Arg377His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 14/22 in silico tools predict a damaging 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. R377C) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: LMNA NM_170707.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8 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]

ACMG classification

Verdict is Pathogenic. Variant got 17 ACMG points.

• 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 Lovd as [Pathogenic].
• 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, 0.969
• PP5: Variant 1-156136094-G-A is Pathogenic according to our data. Variant chr1-156136094-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 14495.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-156136094-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LMNA	NM_170707.4	c.1130G>A	p.Arg377His	missense_variant	6/12	ENST00000368300.9	NP_733821.1
LMNA	NM_005572.4	c.1130G>A	p.Arg377His	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>A	p.Arg377His	missense_variant	6/12	1	NM_170707.4	ENSP00000357283	P1
LMNA	ENST00000677389.1	c.1130G>A	p.Arg377His	missense_variant	6/10		NM_005572.4	ENSP00000503633

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2 Other:1

not provided, no classification provided	literature only	Epithelial Biology; Institute of Medical Biology, Singapore	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 25, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 07, 2018	- -

Sudden unexplained death Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Agnes Ginges Centre for Molecular Cardiology, Centenary Institute

Aug 21, 2018

LMNA Arg377His has been reported in multiple probands and families who have one or more of the associated phenotypes in the 'laminopathy' disease spectrum which includes neuromuscular, cardiac, metabolic disorders and premature aging syndromes (Schneiders et al., 2017; Furuta et al., 2016; Madej-Pilarczyk et al., 2015; Sakiyama et al., 2014; Sylvius et al., 2011; Emerson et al., 2009; Rudenskaya et al., 2008; Benedetti et al., 2007; Rudnik-Schoneborn et al., 2007; van Tintelen et al., 2007; Perrot et al., 2006; Sebillon et al., 2003; Taylor et al., 2003; Muchir et al., 2000) and was found to segregate in multiple affected individuals within several families (Rudnik-Schoneborn et al., 2007; van Tintelen et al., 2007; Perrot et al., 2006; Charniot et al., 2003; Taylor et al., 2003; Muchir et al., 2000). We identified this variant in a proband who died suddenly without any cause on postmortem. The variant is also extremely rare as it absent from the Genome Aggregation Database (http://gnomad.broadinstitute.org/). In silico tools SIFT, PolyPhen2 and MutationTaster all predict this variant to be deleterious. Furthermore multiple functional studies suggest that this variant affects both lamin and emerin protein localisation (Emerson et al., 2009; Reichart et al., 2004; Sebillon et al., 2003; Charniot et al., 2003). In summary, this variant has been reported in many probands within the laminopathy spectrum, has been found to segregate strongly within families, functional studies confirm that the variant disrupts protein function, the variant is also rare, in silico tools predict it to be deleterious and missense variants in LMNA are not only rare but are a known mechanism of disease, therefore we classify LMNA Arg377His as 'pathogenic'. -

Muscular dystrophy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Feb 08, 2013

- -

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 histidine, which is basic and polar, at codon 377 of the LMNA protein (p.Arg377His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant limb-girdle muscular dystrophy with atrioventricular conduction disturbances (LGMD1B) (PMID: 10814726, 12673789, 24990833, 26443318, 27220833). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 14495). 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: 12673789, 19524666). 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: 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. -

Dilated cardiomyopathy 1A Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Clinical Center for Gene Diagnosis and Therapy, Department of Cardiovascular Surgery, The Second Xiangya Hospital of Central South University

Jun 01, 2023

- -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 16, 2020

The p.R377H pathogenic mutation (also known as c.1130G>A), located in coding exon 6 of the LMNA gene, results from a G to A substitution at nucleotide position 1130. The arginine at codon 377 is replaced by histidine, an amino acid with highly similar properties. This variant has been detected in individuals with limb girdle muscular dystrophy type 1B and individuals with dilated cardiomyopathy (DCM) with skeletal myopathies; co-segregation with disease has been reported in affected family members from several families (Muchir A et al. Hum. Mol. Genet., 2000 May;9:1453-9; Taylor MR et al. J Am Coll Cardiol, 2003 Mar;41:771-80; Charniot JC et al. Hum. Mutat., 2003 May;21:473-81; Rudnik-Schöneborn S et al. Neurogenetics, 2007 Apr;8:137-42; Furuta M et al. Neuromuscul. Disord., 2016 09;26:593-7). Functional studies have shown this variant to cause mislocalization of lamin and emerin proteins within the cell, as well as to lead to a reduction in protein interactions (Charniot JC et al. Hum. Mutat., 2003 May;21:473-81; Emerson LJ et al. Biochim. Biophys. Acta, 2009 Aug;1792:810-21). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Emery-Dreifuss muscular dystrophy 2, autosomal dominant Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 01, 2007

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
CardioboostCm	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.97	.;.;.;D;.;.;.;.;D
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.91	D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.67	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.6	H;.;H;H;H;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-5.0	D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D;D;D;D;D;D
Polyphen		1.0	D;.;D;D;.;.;D;.;.
Vest4		0.93
MutPred		0.85		Gain of catalytic residue at L379 (P = 0.1152);Gain of catalytic residue at L379 (P = 0.1152);Gain of catalytic residue at L379 (P = 0.1152);Gain of catalytic residue at L379 (P = 0.1152);Gain of catalytic residue at L379 (P = 0.1152);.;.;.;.;
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		0.92
gMVP		0.95

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; COSMIC: COSV61542300; COSMIC: COSV61542300;