rs58932704
Variant summary
Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2PM5PP2PP3_ModeratePP5_Very_Strong
The NM_170707.4(LMNA):c.1357C>T(p.Arg453Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. R453Q) has been classified as Likely pathogenic.
Frequency
Consequence
NM_170707.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 17 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LMNA | NM_170707.4 | c.1357C>T | p.Arg453Trp | missense_variant | 7/12 | ENST00000368300.9 | |
LMNA | NM_005572.4 | c.1357C>T | p.Arg453Trp | missense_variant | 7/10 | ENST00000677389.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LMNA | ENST00000368300.9 | c.1357C>T | p.Arg453Trp | missense_variant | 7/12 | 1 | NM_170707.4 | P1 | |
LMNA | ENST00000677389.1 | c.1357C>T | p.Arg453Trp | missense_variant | 7/10 | NM_005572.4 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1441370Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 715490
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:8Other:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 31, 2022 | 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) - |
not provided, no classification provided | literature only | Epithelial Biology; Institute of Medical Biology, Singapore | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jan 31, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jun 21, 2022 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Likely pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics and Genomics, Karolinska University Hospital | Nov 07, 2014 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Apr 01, 2022 | LMNA: PS4, PM2, PM5, PM6, PS3:Supporting - |
Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | May 26, 2022 | 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. - |
Emery-Dreifuss muscular dystrophy 2, autosomal dominant Pathogenic:3
Likely pathogenic, criteria provided, single submitter | research | Center for Genetic Medicine Research, Children's National Medical Center | Dec 01, 2015 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 01, 1999 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn | - | 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). - |
Congenital muscular dystrophy due to LMNA mutation Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory of Medical Genetics, National & Kapodistrian University of Athens | Oct 24, 2022 | PM1, PM2, PM5, PP2, PP3, PP5 - |
Pathogenic, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Mar 26, 2024 | - - |
Muscular dystrophy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Feb 08, 2013 | - - |
Charcot-Marie-Tooth disease type 2 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 03, 2023 | 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. - |
Dilated cardiomyopathy 1A Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Feb 19, 2020 | 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. - |
Abnormality of the musculature Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Kariminejad - Najmabadi Pathology & Genetics Center | Jul 10, 2021 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at