rs397517889

Positions:

chr1-156136093-C-T

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM2PM5PP2PP3_StrongPP5_Very_Strong

The NM_170707.4(LMNA):c.1129C>T(p.Arg377Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000124 in 1,613,938 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. R377H) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

LMNA
NM_170707.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12

Conservation

PhyloP100: 3.87

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 chr1-156136094-G-A 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, 0.973

PP5

Variant 1-156136093-C-T is Pathogenic according to our data. 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. Variant chr1-156136093-C-T is described in Lovd as [Pathogenic]. Variant chr1-156136093-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LMNA	NM_170707.4 linkuse as main transcript	c.1129C>T	p.Arg377Cys	missense_variant	6/12	ENST00000368300.9	NP_733821.1
LMNA	NM_005572.4 linkuse as main transcript	c.1129C>T	p.Arg377Cys	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 linkuse as main transcript	c.1129C>T	p.Arg377Cys	missense_variant	6/12	1	NM_170707.4	ENSP00000357283	P1	P02545-1
LMNA	ENST00000677389.1 linkuse as main transcript	c.1129C>T	p.Arg377Cys	missense_variant	6/10		NM_005572.4	ENSP00000503633		P02545-2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

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:

0.000478

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461756

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727186

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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

AF:

0.00000657

AC:

AN:

152182

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74336

show subpopulations

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:

0.000478

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:5

Likely pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 16, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 21, 2023	Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate a damaging effect via disruption of normal protein folding leading to LMNA aggregation (PMID: 34862408); This variant is associated with the following publications: (PMID: 15678000, 21840938, 20474083, 18035086, 10814726, 12920062, 16407522, 19124654, 18646565, 20576434, 24503780, 23183350, 26060040, 27532257, 23062543, 27506821, 12032588, 16386954, 21483645, 31410651, 31296281, 31447099, 30078822, 34930020, 35387801, 37652022, 34363016, 36548481, 35239206, 21632249, 10939567, 34862408) -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Mar 27, 2023	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Mar 18, 2015	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. LMNA p.Arg377Cys Given the case data and lack of presence in general population databases (reviewed below) we consider this variant as likely disease causing. The variant has been seen in at least five unrelated cases with cardiomyopathy or laminopathy in the literature. There is segregation data on family members in the reported cases. Astejada M. et al., 2008 reported c.1129 C>T in one Japanese individual with muscular dystrophy with nuclear envelopathy. No specific details were provided. Komaki H et al., 2011 reported R377C in one female who died at 7 yo from heart failure. She had an unsteady gate and a CK of 1000 at biopsy. Cardiac involvement included DCM diagnosed at 7 yo with an EF of 32%. She had joint contractures of her ankles and no respiratory dysfunction. Sylvius et al., 2011 reported c.1129C>T in two unrelated individuals. One was diagnosed at 42 yo after having difficulty climbing stairs. (S)he had pelvic and muscle weakness, axial muscle wasting, no contractures cardiomyopathy with CD and ICD and was last examined at age 56. The other patient was diagnosed at age 40 after having difficulty climbing stairs. (S)he also had pelvic muscle weakness with cardiac conduction defects and arrhythmia and their last reported evaluation before publication was at age 67. Van Rijsingen et al., 2013 reported this variant in one individual with this variant in their large cohort of LMNA mutation carriers but no individual data was provided. Similar changes at the same amino acid are summarized below: Charniot et al., 2003 reported a family harboring the R377H variant. 12 family members are positive for the R377H variant in lamin A. Of those, 11/12 have a DCM phenotype. The one unaffected individual is the youngest of the mutation positive family members at 21 yo. 4/10 evaluated mutation positive family members have a muscular phenotype, and 1/10 additional family members has a borderline study at age 33 yo. All of the individuals in their 30s and 40s had a reduced ejection fraction (<55%), while those in their 20s had ejection fractions in the 60s. Complete left bundle branch block was found in 5/8 evaluated individuals 4/8 also had some level of AV block (including two individuals who had both LBBB and AVB. 9/12 individuals had some level of AF and 4 had episodes of VT. Every mutation positive family member over the age of 21 had some form of conduction system disease. Muchir et al., 2000 reported a carribean family with the R377H variant. Eight individuals were evaluated. This family reported musculoskeletal, cardiomyopathy and AV conduction system defects. In silico analysis with PolyPhen-2 predicts the variant to be damaging. The argenine at codon is conserved across species, as are neighboring amino acids. Other variants have been reported in association with disease at this codon 377 and nearby codons. In total the variant has not been seen in individuals from publicly available population datasets. There is no variation at codon 377 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on Caucasian and African American individuals (as of October 29, 2014). -

Dilated cardiomyopathy 1A

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Center of Genomic medicine, Geneva, University Hospital of Geneva	Aug 01, 2018	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	May 25, 2017	This c.1129C>T (p.Arg377Cys) variant in the LMNA gene has previously been reported in a 49 year old male with a diagnosis and a family history of DCM [PMID 24503780] and was also detected in a 10 y/o female who died of heart failure, with unsteady gait, diagnosed at the age of 7 with DCM [PMID 21632249]. This variant was also detected in a cohort of patients with muscular dystrophy [PMID 18646565] and a cohort of patients with cardiac disease [PMID 23183350]. Additional variants affecting the same amino acid at position 377 (p.Arg377His and p.Arg377Leu) have been reported in patients with cardiomyopathy and muscular dystrophy. Arginine at position 377 of the LMNA protein is highly conserved in mammals and has not been observed in the ExAC database. While not validated for clinical use, the computer-based algorithms SIFT and Polyphen-2 predict this Arg377Cys change to be deleterious. It is thus interpreted as a likely pathogenic variant. -

Emery-Dreifuss muscular dystrophy 2, autosomal dominant;C1449563:Dilated cardiomyopathy 1A;C2750785:Congenital muscular dystrophy due to LMNA mutation

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Immunology and Genetics Kaiserslautern

Apr 16, 2024

ACMG Criteria: PS4, PM2_P, PM5, PM1, PP1, PP5; Variant was found in heterozygous state -

Charcot-Marie-Tooth disease type 2

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 15, 2024

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 377 of the LMNA protein (p.Arg377Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with cardiomyopathy and muscular dystrophy (PMID: 18646565, 21632249, 21840938, 23183350, 24503780). ClinVar contains an entry for this variant (Variation ID: 48031). 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: 12628721, 12673789, 15053843, 16386954). 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. -

Charcot-Marie-Tooth disease type 2B1

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Eurofins-Biomnis

Sep 23, 2022

- -

Primary dilated cardiomyopathy

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 09, 2016

proposed classification - variant undergoing re-assessment, contact laboratory -

Cardiovascular phenotype

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 29, 2023

The p.R377C pathogenic mutation (also known as c.1129C>T), located in coding exon 6 of the LMNA gene, results from a C to T substitution at nucleotide position 1129. The arginine at codon 377 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been reported in multiple individuals with laminopathies, including dilated cardiomyopathy (DCM), Emery-Dreifuss muscular dystrophy, and limb girdle muscular dystrophy (Deconinck N et al. Neuromuscul Disord, 2010 Aug;20:517-23; Komaki H et al. Neuromuscul Disord, 2011 Aug;21:563-8; Sylvius N et al. FASEB J, 2011 Nov;25:3966-78; Pugh TJ et al. Genet Med, 2014 Aug;16:601-8; Hasselberg NE et al. Eur Heart J, 2018 Mar;39:853-860; Cotta A et al. J Mol Neurosci, 2019 Dec;69:623-627; Krenn M et al. Eur J Neurol, 2022 Jun;29:1815-1824; Pessente GD et al. Front Cardiovasc Med, 2022 Apr;9:823717). Two other alterations at the same codon, p.R377L (c.1130G>T) and p.R377H (c.1130G>A), have been detected in subjects with DCM, as well as in subjects with varying forms of muscular dystrophy, and have been reported to segregate with disease (Muchir A et al. Hum. Mol. Genet., 2000 May;9:1453-9; Ki CS et al. J. Hum. Genet., 2002;47:225-8; Boriani G et al. Stroke, 2003 Apr;34:901-8; Charniot JC et al. Hum. Mutat., 2003 May;21:473-81; Sébillon P et al. J. Med. Genet., 2003 Aug;40:560-7; Rudnik-Schöneborn S et al. Neurogenetics, 2007 Apr;8:137-42; Verdonschot JAJ et al. Circ Genom Precis Med, 2020 10;13:476-487). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This alteration is predicted to be deleterious by BayesDel in silico analysis. 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

0.97

CardioboostCm

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.52

BayesDel_noAF

Pathogenic

0.50

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.98

.;.;.;D;.;.;.;.;D

Eigen

Pathogenic

0.84

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.95

D;D;D;D;D;D;D;D;D

M_CAP

Pathogenic

0.71

MetaRNN

Pathogenic

0.97

D;D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.3

M;.;M;M;M;.;.;.;.

MutationTaster

Benign

1.0

D;D;D;D;D;D;D;D;D

PrimateAI

Pathogenic

0.88

PROVEAN

Pathogenic

-7.9

D;D;D;D;D;D;D;D;D

REVEL

Pathogenic

0.94

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

0.94

MutPred

0.85

Gain of methylation at K378 (P = 0.0166);Gain of methylation at K378 (P = 0.0166);Gain of methylation at K378 (P = 0.0166);Gain of methylation at K378 (P = 0.0166);Gain of methylation at K378 (P = 0.0166);.;.;.;.;

MVP

0.99

MPC

2.4

ClinPred

1.0

GERP RS

5.3

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.8

Varity_R

0.94

gMVP

0.98

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

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