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

dbSNP: rs58932704

Total submissions: 22

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Center for Genetic Medicine Research, Children's National Medical Center	RCV000015565	SCV000265777	likely pathogenic	Emery-Dreifuss muscular dystrophy 2, autosomal dominant	2015-12-01	criteria provided, single submitter	research
GeneDx	RCV000057273	SCV000292719	pathogenic	not provided	2022-10-31	criteria provided, single submitter	clinical testing	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)
Eurofins Ntd Llc (ga)	RCV000057273	SCV000335899	pathogenic	not provided	2018-01-31	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000472112	SCV000548859	pathogenic	Charcot-Marie-Tooth disease type 2	2024-12-12	criteria provided, single submitter	clinical testing	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). 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%. 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.
Genetic Services Laboratory, University of Chicago	RCV000500734	SCV000595631	pathogenic	Muscular dystrophy	2013-02-08	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001095717	SCV001251555	likely pathogenic	Dilated cardiomyopathy 1A	2020-02-19	criteria provided, single submitter	clinical testing	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.
Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn	RCV000015565	SCV001251976	pathogenic	Emery-Dreifuss muscular dystrophy 2, autosomal dominant		criteria provided, single submitter	clinical testing	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).
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000057273	SCV001449797	likely pathogenic	not provided	2014-11-07	criteria provided, single submitter	clinical testing
Kariminejad - Najmabadi Pathology & Genetics Center	RCV001813989	SCV001755496	pathogenic	Abnormality of the musculature	2021-07-10	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000057273	SCV002017167	pathogenic	not provided	2022-06-21	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000057273	SCV002544321	pathogenic	not provided	2022-04-01	criteria provided, single submitter	clinical testing	LMNA: PS4, PM2, PM5, PM6, PS3:Supporting
Athena Diagnostics	RCV000057273	SCV002771306	pathogenic	not provided	2022-05-26	criteria provided, single submitter	clinical testing	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.
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV003313922	SCV004013960	pathogenic	Congenital muscular dystrophy due to LMNA mutation	2022-10-24	criteria provided, single submitter	clinical testing	PM1, PM2, PM5, PP2, PP3, PP5
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV003313922	SCV004806600	pathogenic	Congenital muscular dystrophy due to LMNA mutation	2024-03-26	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004639121	SCV005130629	pathogenic	Cardiovascular phenotype	2024-04-05	criteria provided, single submitter	clinical testing	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.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000015565	SCV005398764	pathogenic	Emery-Dreifuss muscular dystrophy 2, autosomal dominant	2022-09-02	criteria provided, single submitter	clinical testing	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
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV000015565	SCV005416770	pathogenic	Emery-Dreifuss muscular dystrophy 2, autosomal dominant		criteria provided, single submitter	clinical testing	PM2_Supporting+PP3_Moderate+PS4+PM6_Supporting+PP1+PP4
3billion	RCV000015565	SCV005904469	pathogenic	Emery-Dreifuss muscular dystrophy 2, autosomal dominant	2023-10-05	criteria provided, single submitter	clinical testing	The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: Missense variant Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID: 20980393). In silico tool predictions suggest a damaging effect of the variant on gene or gene product [REVEL: 0.88 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.91 (>=0.6, sensitivity 0.72 and precision 0.9)]. The same nucleotide change resulting in the same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000014478 /PMID: 10080180). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 10080180, 20980393, 22326558, 24642510). Different missense changes at the same codon (p.Arg453Gln, p.Arg453Pro) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000066808, VCV000570103 /PMID: 18551513). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
OMIM	RCV000015565	SCV000035830	pathogenic	Emery-Dreifuss muscular dystrophy 2, autosomal dominant	1999-03-01	no assertion criteria provided	literature only
Epithelial Biology; Institute of Medical Biology, Singapore	RCV000057273	SCV000088386	not provided	not provided		no assertion provided	not provided
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000057273	SCV001743435	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000057273	SCV001954947	pathogenic	not provided		no assertion criteria provided	clinical testing