1-156137666-C-T

Variant names:

• chr1-156137666-C-T
• rs56984562
• NM_170707.4:c.1621C>T

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_170707.4(LMNA):​c.1621C>T​(p.Arg541Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000713 in 1,401,750 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R541G) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: LMNA NM_170707.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10 O:1
• Conservation: PhyloP100: 0.895
• Publications: 47 publications found

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 Gene-Disease associations (from GenCC):

• dilated cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• dilated cardiomyopathy 1A

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Ambry Genetics, Orphanet
• familial partial lipodystrophy, Dunnigan type

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae)
• Hutchinson-Gilford progeria syndrome

  Inheritance: AD, SD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• restrictive dermopathy 2

  Inheritance: AR, AD Classification: DEFINITIVE, LIMITED Submitted by: G2P
• Emery-Dreifuss muscular dystrophy 2, autosomal dominant

  Inheritance: SD, AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• atrioventricular block

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• heart-hand syndrome, Slovenian type

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, G2P
• Charcot-Marie-Tooth disease type 2B1

  Inheritance: AR, AD Classification: STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: G2P, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
• Emery-Dreifuss muscular dystrophy 3, autosomal recessive

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• mandibuloacral dysplasia with type A lipodystrophy

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
• atrial fibrillation

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• atypical Werner syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal dominant Emery-Dreifuss muscular dystrophy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• congenital muscular dystrophy due to LMNA mutation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• lethal restrictive dermopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• LMNA-related cardiocutaneous progeria syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal recessive Emery-Dreifuss muscular dystrophy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• dilated cardiomyopathy-hypergonadotropic hypogonadism syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal semi-dominant severe lipodystrophic laminopathy

  Inheritance: SD Classification: SUPPORTIVE Submitted by: Orphanet
• arrhythmogenic right ventricular cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 26 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 chr1-156137666-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 29775.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.918
• PP5: Variant 1-156137666-C-T is Pathogenic according to our data. Variant chr1-156137666-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 48046.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LMNA	NM_170707.4	c.1621C>T	p.Arg541Cys	missense_variant	Exon 10 of 12	ENST00000368300.9	NP_733821.1
LMNA	NM_005572.4	c.1621C>T	p.Arg541Cys	missense_variant	Exon 10 of 10	ENST00000677389.1	NP_005563.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LMNA	ENST00000368300.9	c.1621C>T	p.Arg541Cys	missense_variant	Exon 10 of 12	1	NM_170707.4	ENSP00000357283.4
LMNA	ENST00000677389.1	c.1621C>T	p.Arg541Cys	missense_variant	Exon 10 of 10		NM_005572.4	ENSP00000503633.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.13e-7 AC: 1 AN: 1401750 Hom.: 0 Cov.: 31 AF XY: 0.00000145 AC XY: 1 AN XY: 691498

African (AFR) AF: 0.00 AC: 0 AN: 31938

American (AMR) AF: 0.00 AC: 0 AN: 35756

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25186

East Asian (EAS) AF: 0.00 AC: 0 AN: 36296

South Asian (SAS) AF: 0.00 AC: 0 AN: 79330

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49272

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5674

European-Non Finnish (NFE) AF: 9.26e-7 AC: 1 AN: 1080152

Other (OTH) AF: 0.00 AC: 0 AN: 58146

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4 Other:1

-

Epithelial Biology; Institute of Medical Biology, Singapore

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Dec 16, 2014

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 14, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies examined the effect of p.(R541C) on the nuclear envelope in cultured skin fibroblasts and reported an absence or significant decrease in lamin B1 expression, as well as a lobulated nuclear envelope, in comparison to controls (Muchir et al., 2004); 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: 18031519, 31912959, 30847666, 24375749, 24503780, 19167105, 24623722, 19933576, 23702046, 27532257, 15724423, 22464770, 30165862, 29952368, 31383942, 32458740, 31447099, 32914734, 30975432, 33250842, 14675861, 10939567, 15372542) -

Feb 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

LMNA: PM2, PM5, PP1:Moderate, PS4:Moderate, PP4, PS3:Supporting -

Jun 06, 2016

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: provider interpretation

We consider this variant to be very likely pathogenic and we do feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). The reasons for this classification include strong case data, including de novo occurrence and some segregation data in two families; functional studies supporting pathogenicity; and multiple other reported disease causing variants affecting the same codon. We have seen this variant in a patient with DCM. Testing was performed by Invitae. The variant has been seen in at least 6 unrelated cases of dilated cardiomyopathy and/or arrhythmia (not including this patient's family). Forissier J et al., 2003 reported the R541C variant in a father and daughter with DCM and arrhythmias. R541C occurred de novo in the father in the context of a negative family history in preceding generations. Muchir et al., 2004 reported to be a 29 year-old with DCM and conduction system disease. They performed functional studied in cultured skin fibroblasts and reported an absence or significant decrease in lamin B1 expression and a lobulated nuclear envelope with the R541C variant compared to controls. Hookana et al., 2008 reported the R541C variant in a mother with a history of an aborted SCD and LV hypokinesia and thinning and daughter who died suddenly and was found to have localize LV thinning and fibrosis. The variant was found to have occurred de novo in the mother in the context of a negative family history. Saj M et al., 2010 reported a 19 year old with LV DCM s/p ICD implantation and aborted VFib cardiac arrests, with a family history of SCD. Pugh et al., 2014 reported R541C in two individuals with DCM, one of which also carried a mutation in the LDB3 gene, per the LMM ClinVar entry. Other variants at the same codon (R541H, R541G, R541P, R541S) have been reported in association with dilated cardiomyopathy and other laminopathies, supporting the hypothesis that this codon occurs at a functionally important location in the protein. Per the Invitae report, "This sequence change replaces arginine with cysteine at codon 541 of the LMNA protein (p.Arg541Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine." Please note that the average coverage at this site in ExAC is poor: The mean depth is ~16x, the median depth is 4x, and ~95% of people have ~1x coverage, with ~40% having 5x coverage. The variant was reported online in 2 of 10,695 individuals in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of 6/6/2016). Specifically, the variant was observed in 2 of 4,568 non-Finnish European people. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. -

Dilated cardiomyopathy 1A Pathogenic:2

Aug 27, 2015

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 31, 2018

SIB Swiss Institute of Bioinformatics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

This variant is interpreted as a Likely Pathogenic, for Dilated cardiomyopathy, in Autosomal Dominant manner. The following ACMG Tag(s) were applied: PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PM1 => Located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation (PMID:18035086,16061563,18564364,21085127). PS3 => Well-established functional studies show a deleterious effect (PMID:15372542). -

Laminopathy Pathogenic:1

Oct 09, 2024

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.5, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative, loss of function and gain of function are known mechanisms of disease in this gene. Some missense variants have been reported to result in a toxic gain of function or dominant negative and are associated with childhood-onset disease or skeletal muscle involvement, while other variants have been reported to result in a loss of function and haploinsufficiency, and are associated with adult-onset disease, cardiac disorders or myopathy (PMID: 17377071). (I) 0108 - This gene is associated with both recessive and dominant disease (OMIM). (I) 0112 - The condition associated with this gene has incomplete penetrance. Pathogenic variants have been reported with reduced penetrance in families with Emery-Dreifuss muscular dystrophy and LMNA-related disorders (PMID: 20301609). Age-related penetrance has been reported for LMNA-related dilated cardiomyopathy (PMID: 20301717). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v4) <0.01 (1 heterozygote, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2; 3 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated lamin tail domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by multiple clinical laboratories in ClinVar. This variant has also been observed in unrelated individuals with dilated cardiomyopathy (PMID: 32666643, 29952368). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Charcot-Marie-Tooth disease type 2 Pathogenic:1

Nov 04, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 541 of the LMNA protein (p.Arg541Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with cardiac arrest and left ventricular fibrosis and dilated cardiomyopathy (PMID: 14675861, 15724423, 18031519, 22464770, 24503780, 27532257). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 48046). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt LMNA protein function with a positive predictive value of 95%. This variant disrupts the p.Arg541 amino acid residue in LMNA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22186027, 24623722). 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. -

Primary dilated cardiomyopathy Pathogenic:1

Apr 06, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Arg541Cys variant in LMNA has been identified in 6 individuals with DCM (F orissier 2003, Muchir 2004, Saj 2009, LMM data) and in one individual with sudde n cardiac death (Hookana 2008), occurring de novo in 2 cases (paternity confirme d). It was also shown to segregate with disease in 5 affected relatives from 4 f amilies (Forissier 2003, Hookana 2008, LMM data). It was absent from large popul ation studies. This variant has been shown to cause nuclear lamina abnormalities (Muchir 2004). Computational prediction tools and conservation analysis suggest that this variant may impact the protein and additional variants involving this amino acid, p.Arg541Ser and p.Arg541His, have been associated with DCM. In summ ary, this variant meets our criteria to be classified as pathogenic based upon c ase observations, de novo occurrences, segregation studies, absence from control s, and functional evidence. ACMG/AMP Criteria applied: PM6_Strong; PM2; PM5; PS4 _Moderate; PP1_Moderate; PP3. -

Cardiovascular phenotype Pathogenic:1

Jun 01, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R541C pathogenic mutation (also known as c.1621C>T), located in coding exon 10 of the LMNA gene, results from a C to T substitution at nucleotide position 1621. The arginine at codon 541 is replaced by cysteine, an amino acid with highly dissimilar properties. This mutation was reported in a Moroccan family with dilated cardiomyopathy (DCM), and co-segregation was observed in several affected family members (Adadi N et al. Anatol J Cardiol, 2018 Jul;20:65-68). This mutation has been associated with severe ventricular arrhythmia, left ventricular wall motion abnormalities, dilated cardiomyopathy (DCM) with significant left ventricular segmental contractility defects, and sudden cardiac death (Forissier JF et al. Eur. J. Heart Fail., 2003 Dec;5:821-5; Hookana E et al. J. Cardiovasc. Electrophysiol., 2008 Jul;19:743-7; Saj M et al. Int. J. Cardiol., 2010 Oct;144:e51-3). The mutation was shown to be associated with abnormal nuclear envelop folding in two independent studies (Muchir A et al. Muscle Nerve, 2004 Oct;30:444-50; Hookana E et al, 2008). Additionally, alterations at the same amino acid position, p.R541S (Sylvius N et al. J. Med. Genet., 2005 Aug;42:639-47), p.R541G (Maek LA et al. J. Hum. Genet., 2011 Jan;56:83-6), p.R541P (van Tintelen JP et al. Am. Heart J., 2007 Dec;154:1130-9), and p.R541H (Rudenskaya GE et al. Clin. Genet., 2008 Aug;74:127-33) have also been reported in families with cardiomyopathy. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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	0.86
CardioboostCm	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.97	.;.;D;.;.;.;.
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D;D
M_CAP	Pathogenic	0.74	D
MetaRNN	Pathogenic	0.92	D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.8	M;.;M;M;.;.;.
PhyloP100		0.90
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-6.6	D;.;D;D;D;D;D
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	D;.;D;D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D;D
Polyphen		1.0	D;.;D;.;.;D;.
Vest4		0.83
MutPred		0.73		Gain of methylation at K542 (P = 0.0127);.;Gain of methylation at K542 (P = 0.0127);Gain of methylation at K542 (P = 0.0127);.;.;.;
MVP		0.98
MPC		1.3
ClinPred		1.0	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.78
gMVP		0.95
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs56984562; hg19: chr1-156107457;