VCV000014478.71 - ClinVar

NM_170707.4(LMNA):c.1357C>T (p.Arg453Trp)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(20)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_170707.4(LMNA):c.1357C>T (p.Arg453Trp)

Variation ID: 14478 Accession: VCV000014478.71

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1q22 1: 156136413 (GRCh38) [ NCBI UCSC ] 1: 156106204 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Oct 19, 2013	Nov 24, 2024	Apr 5, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_170707.4:c.1357C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_733821.1:p.Arg453Trp	missense
NM_005572.4:c.1357C>T MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_005563.1:p.Arg453Trp	missense
NM_001257374.3:c.1021C>T	NP_001244303.1:p.Arg341Trp	missense
NM_001282624.2:c.1114C>T	NP_001269553.1:p.Arg372Trp	missense
NM_001282625.2:c.1357C>T	NP_001269554.1:p.Arg453Trp	missense
NM_001282626.2:c.1357C>T	NP_001269555.1:p.Arg453Trp	missense
NM_170708.4:c.1357C>T	NP_733822.1:p.Arg453Trp	missense
NC_000001.11:g.156136413C>T
NC_000001.10:g.156106204C>T
NG_008692.2:g.58841C>T
LRG_254:g.58841C>T
LRG_254t2:c.1357C>T
	P02545:p.Arg453Trp

... more HGVS ... less HGVS

Protein change

R453W, R341W, R372W

Other names

Canonical SPDI

NC_000001.11:156136412:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

functionally_abnormal; Sequence Ontology [ SO:0002218]

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

OMIM: 150330.0002 dbSNP: rs58932704 ClinGen: CA017033 UniProtKB: P02545#VAR_009988 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
LMNA		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	1847	2129

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Emery-Dreifuss muscular dystrophy 2, autosomal dominant	Pathogenic/Likely pathogenic (4)	criteria provided, multiple submitters, no conflicts	Sep 2, 2022	RCV000015565.37
not provided	Pathogenic/Likely pathogenic (9)	criteria provided, multiple submitters, no conflicts	Oct 31, 2022	RCV000057273.39
Muscular dystrophy	Pathogenic (1)	criteria provided, single submitter	Feb 8, 2013	RCV000500734.7
Charcot-Marie-Tooth disease type 2	Pathogenic (1)	criteria provided, single submitter	Oct 3, 2023	RCV000472112.15
Dilated cardiomyopathy 1A	Likely pathogenic (1)	criteria provided, single submitter	Feb 19, 2020	RCV001095717.6
Abnormality of the musculature	Pathogenic (1)	criteria provided, single submitter	Jul 10, 2021	RCV001813989.3
Congenital muscular dystrophy due to LMNA mutation	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Mar 26, 2024	RCV003313922.4
Cardiovascular phenotype	Pathogenic (1)	criteria provided, single submitter	Apr 5, 2024	RCV004639121.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Likely pathogenic (Nov 07, 2014)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics and Genomics, Karolinska University Hospital Accession: SCV001449797.1 First in ClinVar: Dec 11, 2020 Last updated: Dec 11, 2020	Number of individuals with the variant: 1
Pathogenic (May 26, 2022)	criteria provided, single submitter (Athena Diagnostics Criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Athena Diagnostics Accession: SCV002771306.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022	Publications: PubMed (19) PubMed: 10939567‚ 15372542‚ 18396274‚ 24642510‚ 24375749‚ 10739764‚ 11503164‚ 14684700‚ 20848652‚ 11731280‚ 23217256‚ 24623722‚ 25343322‚ 23990565‚ 18646565‚ 26575312‚ 19070492‚ 25210889‚ 17967828 Comment: This variant has been identified heterozygous in multiple unrelated individuals with Emery-Dreifuss Muscular Dystrophy (EDMD), suggesting dominant inheritance. This variant has not been reported in … (more) This variant has been identified heterozygous in multiple unrelated individuals with Emery-Dreifuss Muscular Dystrophy (EDMD), suggesting dominant inheritance. This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)). Computational tools predict that this variant is damaging. (less)
Likely pathogenic (Dec 01, 2015)	criteria provided, single submitter (Punetha et al. (J Neuromuscul Dis. 2016)) Method: research	Emery-Dreifuss muscular dystrophy 2, autosomal dominant Affected status: yes Allele origin: unknown	Center for Genetic Medicine Research, Children's National Medical Center Accession: SCV000265777.2 First in ClinVar: Jul 01, 2016 Last updated: Dec 06, 2016	Publications: PubMed (1) PubMed: 27854218
Pathogenic (Feb 08, 2013)	criteria provided, single submitter (ACMG Guidelines, 2007) Method: clinical testing	Muscular dystrophy Affected status: yes Allele origin: germline	Genetic Services Laboratory, University of Chicago Accession: SCV000595631.1 First in ClinVar: Aug 28, 2017 Last updated: Aug 28, 2017
Pathogenic (Jan 31, 2018)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000335899.4 First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018	Publications: PubMed (4) PubMed: 10080180‚ 11731280‚ 20848652‚ 25948554 Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=LMNA http://www.lovd.nl/LMNA http://www.lovd.nl/LMNA Number of individuals with the variant: 8 Sex: mixed
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Emery-Dreifuss muscular dystrophy 2, autosomal dominant (Autosomal dominant inheritance) Affected status: yes Allele origin: de novo	Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn Accession: SCV001251976.1 First in ClinVar: Jun 18, 2020 Last updated: Jun 18, 2020	Comment: The presence of a disease-causing variant was detected in exon 7 of the LMNA gene. The name of the variant is: NM_170707:c.1357C> T;p.Arg453Trp. In the … (more) The presence of a disease-causing variant was detected in exon 7 of the LMNA gene. The name of the variant is: NM_170707:c.1357C> T;p.Arg453Trp. In the parents, this variant could not be detected in 21 reads each, which is why it is very likely that the patient developed it anew (de novo). This variant is not listed in population-based databases (gnomAD, ExAC, EVS and 1000Genomes). In dbSNP it is listed under the rs number rs58932704 . In the phanotype-related databases LOVD, HGMD and ClinVar the variant is already listed several times and is generally considered to be mainly pathogenic, but also probably pathogenic. The mutation prediction programs MutationTaster, SIFT, PROVEAN and PolyPhen-2 assess the variant as pathogenic, the CADD score is 34. In order to assess the possible disturbance of splice behavior by the above-mentioned variant, we have used various programs for the prediction of splice sites and splice enhancers with the aid of the Alamut software. The in-silica analysis does not provide any significant indication of a change in splice1 behavior. Functional studies have shown significant effects of this variant on protein function (e.g. PMID 21173262, 14749366, 20980393, 25948554). The ACMG classification for this variant is: pathogenic (class 5; PS2 PS3 PM2 PP3 PP5). (less) Clinical Features: Spinal rigidity (present) , Kyphosis (present) , Lumbar scoliosis (present) , Elbow flexion contracture (present) Sex: male
Pathogenic (Jul 10, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Abnormality of the musculature Affected status: yes Allele origin: de novo	Kariminejad - Najmabadi Pathology & Genetics Center Accession: SCV001755496.1 First in ClinVar: Jan 22, 2022 Last updated: Jan 22, 2022
Likely pathogenic (Feb 19, 2020)	criteria provided, single submitter (ICSLVariantClassificationCriteria RUGD 01 April 2020) Method: clinical testing	Dilated cardiomyopathy 1A Affected status: unknown Allele origin: unknown	Illumina Laboratory Services, Illumina Accession: SCV001251555.2 First in ClinVar: May 31, 2020 Last updated: Mar 04, 2023	Publications: PubMed (5) PubMed: 29057633‚ 25987458‚ 18646565‚ 10080180‚ 14749366 Comment: The LMNA c.1357C>T (p.Arg453Trp) variant is a missense variant. A literature search was performed for the gene, cDNA change, and amino acid change. No publications … (more) The LMNA c.1357C>T (p.Arg453Trp) variant is a missense variant. A literature search was performed for the gene, cDNA change, and amino acid change. No publications reporting this variant in association with isolated dilated cardiomyopathy were found based on this search. However, multiple publications report the variant in association with various types of muscular dystrophy with cardiac manifestations (Bonne et al. 1999; Astejada et al. 2007; Dai et al. 2015; Lee et al. 2017). The variant is not found in the Genome Aggregation Database in a region of good sequencing coverage, which suggests the variant is rare. Functional studies in mouse myoblast C2C12 cells expressing the p.Arg453Trp variant showed poor cell differentiation, improper cell cycle exit, and excessive committment to apoptosis (Favreau et al. 2004). The Arg453 residue lies within the laminin tail domain, a region that may be involved in protein or DNA binding, and in silico analyses suggest the variant is deleterious. Based on the evidence and the application of the ACMG criteria, the p.Arg453Trp variant is classified as likely pathogenic for dilated cardiomyopathy. (less)
Pathogenic (Oct 31, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000292719.11 First in ClinVar: Jul 24, 2016 Last updated: Apr 23, 2023	Comment: Identified in patients with autosomal dominant Emery-Dreifuss muscular dystrophy, limb-girdle muscular dystrophy 1B, and congenital fiber type disproportion myopathy in published literature (Bonne et al., … (more) Identified in patients with autosomal dominant Emery-Dreifuss muscular dystrophy, limb-girdle muscular dystrophy 1B, and congenital fiber type disproportion myopathy in published literature (Bonne et al., 1999; Mitsuhashi et al., 2010; Kajino et al., 2014); Published functional studies demonstrate the R453W variant alters lamin A protein binding characteristics, and cells expressing the variant exhibit structural abnormalities as well as anomalous differentiation and proliferation (Depreux et al., 2015; Favreau et al., 2004; Folker et al., 2011); 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: 11503164, 18396274, 23427149, 20848652, 18646565, 11731280, 34440373, 27363342, 34862408, 24375749, 22326558, 19524666, 11792809, 21173262, 13129702, 25948554, 20980393, 24907107, 30199159, 28214269, 28987496, 25987458, 24642510, 29057633, 27854218, 23891399, 18551515, 30912254, 30764827, 30107846, 31498906, 32154989, 32576226, 31127727, 34240052, 33502018, 32571898, 32381727, 32140910, 33146414, 12783988, 33084218, 32528171, 33124102, 35741838, 35723113, 16809772, 10080180, 14749366, 10939567) (less)
Pathogenic (Oct 24, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Congenital muscular dystrophy due to LMNA mutation Affected status: yes Allele origin: germline	Laboratory of Medical Genetics, National & Kapodistrian University of Athens Accession: SCV004013960.1 First in ClinVar: Jul 22, 2023 Last updated: Jul 22, 2023	Comment: PM1, PM2, PM5, PP2, PP3, PP5
Pathogenic (Jun 21, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV002017167.3 First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024
Pathogenic (Oct 03, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Charcot-Marie-Tooth disease type 2 Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000548859.11 First in ClinVar: Apr 17, 2017 Last updated: Feb 20, 2024	Publications: PubMed (9) PubMed: 28492532‚ 10080180‚ 20980393‚ 22326558‚ 24642510‚ 14749366‚ 18396274‚ 21173262‚ 18551515 Comment: This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 453 of the LMNA protein … (more) This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 453 of the LMNA protein (p.Arg453Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant LMNA-related conditions (PMID: 10080180, 20980393, 22326558, 24642510). ClinVar contains an entry for this variant (Variation ID: 14478). 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. Experimental studies have shown that this missense change affects LMNA function (PMID: 14749366, 18396274, 21173262). This variant disrupts the p.Arg453 amino acid residue in LMNA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18551515). 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. (less)
Pathogenic (Mar 26, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Congenital muscular dystrophy due to LMNA mutation Affected status: unknown Allele origin: germline	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center Accession: SCV004806600.1 First in ClinVar: Apr 06, 2024 Last updated: Apr 06, 2024
Pathogenic (Apr 05, 2024)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cardiovascular phenotype Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV005130629.1 First in ClinVar: Aug 11, 2024 Last updated: Aug 11, 2024	Publications: PubMed (12) PubMed: 10080180‚ 10739764‚ 11503164‚ 14749366‚ 20848652‚ 20980393‚ 22326558‚ 27363342‚ 30107846‚ 31127727‚ 33502018‚ 36253810 Comment: The p.R453W pathogenic mutation (also known as c.1357C>T), located in coding exon 7 of the LMNA gene, results from a C to T substitution at … (more) The p.R453W pathogenic mutation (also known as c.1357C>T), located in coding exon 7 of the LMNA gene, results from a C to T substitution at nucleotide position 1357. The arginine at codon 453 is replaced by tryptophan, an amino acid with dissimilar properties. This variant was reported in multiple individuals with features consistent with laminopathies, most commonly Emery-Dreifuss muscular dystrophy with or without cardiac manifestations, has been reported to occur de novo in affected cases, and has also shown segregation with disease features in families (Bonne G et al. Nat Genet, 1999 Mar;21:285-8; Raffaele Di Barletta M et al. Am J Hum Genet, 2000 Apr;66:1407-12; Brown CA et al. Am J Med Genet, 2001 Sep;102:359-67; Favreau C et al. Mol Cell Biol, 2004 Feb;24:1481-92; Mitsuhashi H et al. J Cell Sci, 2010 Nov;123:3893-900; Scharner J et al. Hum Mutat, 2011 Feb;32:152-67; Magagnotti C et al. Biochim Biophys Acta, 2012 Jun;1822:970-9; Park HJ et al. Clin Genet, 2017 Mar;91:403-410; Wang L et al. Orphanet J Rare Dis, 2018 Aug;13:133; Westra D et al. J Neuromuscul Dis, 2019;6:241-258; Eldin AJ et al. Clin Endocrinol (Oxf), 2021 Jun;94:1043-1053; Iskandar K et al. BMC Pediatr, 2022 Oct;22:601). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this variant is interpreted as a disease-causing mutation. (less)
Pathogenic (Apr 01, 2022)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV002544321.16 First in ClinVar: Jul 09, 2022 Last updated: Oct 20, 2024	Comment: LMNA: PS4, PM2, PM5, PM6, PS3:Supporting Number of individuals with the variant: 1
Pathogenic (Sep 02, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Emery-Dreifuss muscular dystrophy 2, autosomal dominant (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute Additional submitter: Shariant Australia, Australian Genomics Accession: SCV005398764.1 First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024	Publications: PubMed (4) PubMed: 10739764‚ 17377071‚ 20848652‚ 32571898 Comment: Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative, loss of function and gain … (more) Based on the classification scheme VCGS_Germline_v1.3.4, 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. However, a clear genotype-phenotpe correlation is yet to be established. (I) 0112 - The condition associated with this gene has incomplete penetrance. Emery-Dreifuss muscular dystrophy has been reported to have reduced penetrance (GeneReviews). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to tryptophan. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (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. It is frequently reported in individuals with autosomal dominant Emery-Dreifuss muscular dystrophy 2 (MIM#181350), including de novo events (PMID: 10739764, 20848652, 32571898; ClinVar). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
Pathogenic (Mar 01, 1999)	no assertion criteria provided Method: literature only	EMERY-DREIFUSS MUSCULAR DYSTROPHY 2, AUTOSOMAL DOMINANT Affected status: not provided Allele origin: germline	OMIM Accession: SCV000035830.5 First in ClinVar: Apr 04, 2013 Last updated: Mar 15, 2022	Publications: PubMed (1) PubMed: 10080180 Comment on evidence: In a family with autosomal dominant Emery-Dreifuss muscular dystrophy (EDMD2; 181350), Bonne et al. (1999) demonstrated a C-to-T transition in exon 7 of the LMNA … (more) In a family with autosomal dominant Emery-Dreifuss muscular dystrophy (EDMD2; 181350), Bonne et al. (1999) demonstrated a C-to-T transition in exon 7 of the LMNA gene, resulting in an arg453-to-trp (R453W) substitution. (less)
Likely pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001743435.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001954947.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021
not provided (-)	no classification provided Method: not provided	not provided Affected status: not provided Allele origin: not provided	Epithelial Biology; Institute of Medical Biology, Singapore Accession: SCV000088386.1 First in ClinVar: Oct 19, 2013 Last updated: Oct 19, 2013
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Comment:

This variant has been identified heterozygous in multiple unrelated individuals with Emery-Dreifuss Muscular Dystrophy (EDMD), suggesting dominant inheritance. This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)). Computational tools predict that this variant is damaging.

Comment:

The presence of a disease-causing variant was detected in exon 7 of the LMNA gene. The name of the variant is: NM_170707:c.1357C> T;p.Arg453Trp. In the parents, this variant could not be detected in 21 reads each, which is why it is very likely that the patient developed it anew (de novo). This variant is not listed in population-based databases (gnomAD, ExAC, EVS and 1000Genomes). In dbSNP it is listed under the rs number rs58932704 . In the phanotype-related databases LOVD, HGMD and ClinVar the variant is already listed several times and is generally considered to be mainly pathogenic, but also probably pathogenic. The mutation prediction programs MutationTaster, SIFT, PROVEAN and PolyPhen-2 assess the variant as pathogenic, the CADD score is 34. In order to assess the possible disturbance of splice behavior by the above-mentioned variant, we have used various programs for the prediction of splice sites and splice enhancers with the aid of the Alamut software. The in-silica analysis does not provide any significant indication of a change in splice1 behavior. Functional studies have shown significant effects of this variant on protein function (e.g. PMID 21173262, 14749366, 20980393, 25948554). The ACMG classification for this variant is: pathogenic (class 5; PS2 PS3 PM2 PP3 PP5).

Comment:

The LMNA c.1357C>T (p.Arg453Trp) variant is a missense variant. A literature search was performed for the gene, cDNA change, and amino acid change. No publications reporting this variant in association with isolated dilated cardiomyopathy were found based on this search. However, multiple publications report the variant in association with various types of muscular dystrophy with cardiac manifestations (Bonne et al. 1999; Astejada et al. 2007; Dai et al. 2015; Lee et al. 2017). The variant is not found in the Genome Aggregation Database in a region of good sequencing coverage, which suggests the variant is rare. Functional studies in mouse myoblast C2C12 cells expressing the p.Arg453Trp variant showed poor cell differentiation, improper cell cycle exit, and excessive committment to apoptosis (Favreau et al. 2004). The Arg453 residue lies within the laminin tail domain, a region that may be involved in protein or DNA binding, and in silico analyses suggest the variant is deleterious. Based on the evidence and the application of the ACMG criteria, the p.Arg453Trp variant is classified as likely pathogenic for dilated cardiomyopathy.

Comment:

Identified in patients with autosomal dominant Emery-Dreifuss muscular dystrophy, limb-girdle muscular dystrophy 1B, and congenital fiber type disproportion myopathy in published literature (Bonne et al., 1999; Mitsuhashi et al., 2010; Kajino et al., 2014); Published functional studies demonstrate the R453W variant alters lamin A protein binding characteristics, and cells expressing the variant exhibit structural abnormalities as well as anomalous differentiation and proliferation (Depreux et al., 2015; Favreau et al., 2004; Folker et al., 2011); 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: 11503164, 18396274, 23427149, 20848652, 18646565, 11731280, 34440373, 27363342, 34862408, 24375749, 22326558, 19524666, 11792809, 21173262, 13129702, 25948554, 20980393, 24907107, 30199159, 28214269, 28987496, 25987458, 24642510, 29057633, 27854218, 23891399, 18551515, 30912254, 30764827, 30107846, 31498906, 32154989, 32576226, 31127727, 34240052, 33502018, 32571898, 32381727, 32140910, 33146414, 12783988, 33084218, 32528171, 33124102, 35741838, 35723113, 16809772, 10080180, 14749366, 10939567)

Comment:

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 453 of the LMNA protein (p.Arg453Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant LMNA-related conditions (PMID: 10080180, 20980393, 22326558, 24642510). ClinVar contains an entry for this variant (Variation ID: 14478). 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. Experimental studies have shown that this missense change affects LMNA function (PMID: 14749366, 18396274, 21173262). This variant disrupts the p.Arg453 amino acid residue in LMNA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18551515). 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.

Comment:

The p.R453W pathogenic mutation (also known as c.1357C>T), located in coding exon 7 of the LMNA gene, results from a C to T substitution at nucleotide position 1357. The arginine at codon 453 is replaced by tryptophan, an amino acid with dissimilar properties. This variant was reported in multiple individuals with features consistent with laminopathies, most commonly Emery-Dreifuss muscular dystrophy with or without cardiac manifestations, has been reported to occur de novo in affected cases, and has also shown segregation with disease features in families (Bonne G et al. Nat Genet, 1999 Mar;21:285-8; Raffaele Di Barletta M et al. Am J Hum Genet, 2000 Apr;66:1407-12; Brown CA et al. Am J Med Genet, 2001 Sep;102:359-67; Favreau C et al. Mol Cell Biol, 2004 Feb;24:1481-92; Mitsuhashi H et al. J Cell Sci, 2010 Nov;123:3893-900; Scharner J et al. Hum Mutat, 2011 Feb;32:152-67; Magagnotti C et al. Biochim Biophys Acta, 2012 Jun;1822:970-9; Park HJ et al. Clin Genet, 2017 Mar;91:403-410; Wang L et al. Orphanet J Rare Dis, 2018 Aug;13:133; Westra D et al. J Neuromuscul Dis, 2019;6:241-258; Eldin AJ et al. Clin Endocrinol (Oxf), 2021 Jun;94:1043-1053; Iskandar K et al. BMC Pediatr, 2022 Oct;22:601). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this variant is interpreted as a disease-causing mutation.

Comment:

Based on the classification scheme VCGS_Germline_v1.3.4, 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. However, a clear genotype-phenotpe correlation is yet to be established. (I) 0112 - The condition associated with this gene has incomplete penetrance. Emery-Dreifuss muscular dystrophy has been reported to have reduced penetrance (GeneReviews). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to tryptophan. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (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. It is frequently reported in individuals with autosomal dominant Emery-Dreifuss muscular dystrophy 2 (MIM#181350), including de novo events (PMID: 10739764, 20848652, 32571898; ClinVar). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

Germline Functional Evidence

Functional Help The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence	Method Help A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter.	Result Help A brief description of the result of this method for this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
functionally_abnormal (SO:0002218)			Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn Accession: SCV001251976.1

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Autosomal dominant Emery-Dreifuss muscular dystrophy caused by a mutation in the lamin A/C gene identified by exome sequencing: a case report.	Iskandar K	BMC pediatrics	2022	PMID: 36253810
Cardiac phenotype in familial partial lipodystrophy.	Eldin AJ	Clinical endocrinology	2021	PMID: 33502018
Clinical spectrum and genetic variations of LMNA-related muscular dystrophies in a large cohort of Chinese patients.	Fan Y	Journal of medical genetics	2021	PMID: 32571898
Panel-Based Exome Sequencing for Neuromuscular Disorders as a Diagnostic Service.	Westra D	Journal of neuromuscular diseases	2019	PMID: 31127727
The clinical spectrum and genetic variability of limb-girdle muscular dystrophy in a cohort of Chinese patients.	Wang L	Orphanet journal of rare diseases	2018	PMID: 30107846
Early-Onset LMNA-Associated Muscular Dystrophy with Later Involvement of Contracture.	Lee Y	Journal of clinical neurology (Seoul, Korea)	2017	PMID: 29057633
Discovery of pathogenic variants in a large Korean cohort of inherited muscular disorders.	Park HJ	Clinical genetics	2017	PMID: 27363342
Targeted Re-Sequencing Emulsion PCR Panel for Myopathies: Results in 94 Cases.	Punetha J	Journal of neuromuscular diseases	2016	PMID: 27854218
Cardiac pacing in 21 patients with Emery-Dreifuss muscular dystrophy: a single-centre study with a 39-year follow-up.	Steckiewicz R	Kardiologia polska	2016	PMID: 26575312
A comprehensive genetic diagnosis of Chinese muscular dystrophy and congenital myopathy patients by targeted next-generation sequencing.	Dai Y	Neuromuscular disorders : NMD	2015	PMID: 25987458
Disruption of the lamin A and matrin-3 interaction by myopathic LMNA mutations.	Depreux FF	Human molecular genetics	2015	PMID: 25948554
Characterization of unfolding mechanism of human lamin A Ig fold by single-molecule force spectroscopy-implications in EDMD.	Bera M	Biochemistry	2014	PMID: 25343322
Muscular dystrophy-associated SUN1 and SUN2 variants disrupt nuclear-cytoskeletal connections and myonuclear organization.	Meinke P	PLoS genetics	2014	PMID: 25210889
Congenital fiber type disproportion myopathy caused by LMNA mutations.	Kajino S	Journal of the neurological sciences	2014	PMID: 24642510
Systematic identification of pathological lamin A interactors.	Dittmer TA	Molecular biology of the cell	2014	PMID: 24623722
Mapping disease-related missense mutations in the immunoglobulin-like fold domain of lamin A/C reveals novel genotype-phenotype associations for laminopathies.	Scharner J	Proteins	2014	PMID: 24375749
Nuclear lamin-A scales with tissue stiffness and enhances matrix-directed differentiation.	Swift J	Science (New York, N.Y.)	2013	PMID: 23990565
Resveratrol rescues SIRT1-dependent adult stem cell decline and alleviates progeroid features in laminopathy-based progeria.	Liu B	Cell metabolism	2012	PMID: 23217256
Protein profiling reveals energy metabolism and cytoskeletal protein alterations in LMNA mutation carriers.	Magagnotti C	Biochimica et biophysica acta	2012	PMID: 22326558
Lamin A variants that cause striated muscle disease are defective in anchoring transmembrane actin-associated nuclear lines for nuclear movement.	Folker ES	Proceedings of the National Academy of Sciences of the United States of America	2011	PMID: 21173262
Novel LMNA mutations in patients with Emery-Dreifuss muscular dystrophy and functional characterization of four LMNA mutations.	Scharner J	Human mutation	2011	PMID: 20848652
Specific phosphorylation of Ser458 of A-type lamins in LMNA-associated myopathy patients.	Mitsuhashi H	Journal of cell science	2010	PMID: 20980393
Nuclear changes in skeletal muscle extend to satellite cells in autosomal dominant Emery-Dreifuss muscular dystrophy/limb-girdle muscular dystrophy 1B.	Park YE	Neuromuscular disorders : NMD	2009	PMID: 19070492
Bayesian latent class models with conditionally dependent diagnostic tests: a case study.	Menten J	Statistics in medicine	2008	PMID: 18551515
Expression of the myodystrophic R453W mutation of lamin A in C2C12 myoblasts causes promoter-specific and global epigenetic defects.	Håkelien AM	Experimental cell research	2008	PMID: 18396274
Emerinopathy and laminopathy clinical, pathological and molecular features of muscular dystrophy with nuclear envelopathy in Japan.	Astejada MN	Acta myologica : myopathies and cardiomyopathies : official journal of the Mediterranean Society of Myology	2007	PMID: 18646565
'Unexpected' sudden death avoided by implantable cardioverter defibrillator in Emery Dreifuss patient.	Golzio PG	Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology	2007	PMID: 17967828
Phenotypic clustering of lamin A/C mutations in neuromuscular patients.	Benedetti S	Neurology	2007	PMID: 17377071
Nuclear envelope alterations in fibroblasts from patients with muscular dystrophy, cardiomyopathy, and partial lipodystrophy carrying lamin A/C gene mutations.	Muchir A	Muscle & nerve	2004	PMID: 15372542
Expression of a mutant lamin A that causes Emery-Dreifuss muscular dystrophy inhibits in vitro differentiation of C2C12 myoblasts.	Favreau C	Molecular and cellular biology	2004	PMID: 14749366
Mutation analysis of the lamin A/C gene (LMNA) among patients with different cardiomuscular phenotypes.	Vytopil M	Journal of medical genetics	2003	PMID: 14684700
Autosomal dominant Emery-Dreifuss muscular dystrophy: a new family with late diagnosis.	Colomer J	Neuromuscular disorders : NMD	2002	PMID: 11731280
Novel and recurrent mutations in lamin A/C in patients with Emery-Dreifuss muscular dystrophy.	Brown CA	American journal of medical genetics	2001	PMID: 11503164
Clinical and molecular genetic spectrum of autosomal dominant Emery-Dreifuss muscular dystrophy due to mutations of the lamin A/C gene.	Bonne G	Annals of neurology	2000	PMID: 10939567
Different mutations in the LMNA gene cause autosomal dominant and autosomal recessive Emery-Dreifuss muscular dystrophy.	Raffaele Di Barletta M	American journal of human genetics	2000	PMID: 10739764
Mutations in the gene encoding lamin A/C cause autosomal dominant Emery-Dreifuss muscular dystrophy.	Bonne G	Nature genetics	1999	PMID: 10080180
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=LMNA	-	-	-	-
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Text-mined citations for rs58932704 ...

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Record last updated Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NM_170707.4(LMNA):c.1357C>T (p.Arg453Trp)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs58932704 ...