rs58932704

Variant names:

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

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

LMNA
NM_170707.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:21O:1

Conservation

PhyloP100: 2.00

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.

PM1

In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 10 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 chr1-156136414-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 66808.Status of the report is criteria_provided_single_submitter, 1 stars.

PP2

Missense variant in the LMNA gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 178 curated pathogenic missense variants (we use a threshold of 10). The gene has 69 curated benign missense variants. Gene score misZ: 2.3673 (below the threshold of 3.09). Trascript score misZ: 3.0905 (above the threshold of 3.09). GenCC associations: The gene is linked to 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, 0.908

PP5

Variant 1-156136413-C-T is Pathogenic according to our data. Variant chr1-156136413-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 14478.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-156136413-C-T is described in Lovd as [Likely_pathogenic]. Variant chr1-156136413-C-T is described in Lovd as [Pathogenic]. Variant chr1-156136413-C-T is described in Lovd as [Likely_pathogenic]. Variant chr1-156136413-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LMNA	NM_170707.4 link	c.1357C>T	p.Arg453Trp	missense_variant	Exon 7 of 12	ENST00000368300.9	NP_733821.1	P02545-1A0A384MQX1
LMNA	NM_005572.4 link	c.1357C>T	p.Arg453Trp	missense_variant	Exon 7 of 10	ENST00000677389.1	NP_005563.1	P02545-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LMNA	ENST00000368300.9 link	c.1357C>T	p.Arg453Trp	missense_variant	Exon 7 of 12	1	NM_170707.4	ENSP00000357283.4		P02545-1
LMNA	ENST00000677389.1 link	c.1357C>T	p.Arg453Trp	missense_variant	Exon 7 of 10		NM_005572.4	ENSP00000503633.1		P02545-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1441370

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

715490

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:21Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:8Other:1

May 26, 2022

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

Apr 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

LMNA: PS4, PM2, PM5, PM6, PS3:Supporting -

Jun 21, 2022

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 07, 2014

Clinical Genetics and Genomics, Karolinska University Hospital

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Epithelial Biology; Institute of Medical Biology, Singapore

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Oct 31, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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) -

Jan 31, 2018

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Emery-Dreifuss muscular dystrophy 2, autosomal dominant

Pathogenic:6

Mar 01, 1999

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Dec 01, 2015

Center for Genetic Medicine Research, Children's National Medical Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2_Supporting+PP3_Moderate+PS4+PM6_Supporting+PP1+PP4 -

Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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). -

Oct 05, 2023

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

Sep 02, 2022

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_v1.3.4, 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 -

Congenital muscular dystrophy due to LMNA mutation

Pathogenic:2

Oct 24, 2022

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM1, PM2, PM5, PP2, PP3, PP5 -

Mar 26, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Muscular dystrophy

Pathogenic:1

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Charcot-Marie-Tooth disease type 2

Pathogenic:1

Dec 12, 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 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. -

Dilated cardiomyopathy 1A

Pathogenic:1

Feb 19, 2020

Illumina Laboratory Services, Illumina

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

Cardiovascular phenotype

Pathogenic:1

Apr 05, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

Abnormality of the musculature

Pathogenic:1

Jul 10, 2021

Kariminejad - Najmabadi Pathology & Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.78

CardioboostCm

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.54

BayesDel_noAF

Pathogenic

0.53

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.99

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

Eigen

Pathogenic

0.79

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.91

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

M_CAP

Pathogenic

0.59

MetaRNN

Pathogenic

0.91

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

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.4

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

PrimateAI

Uncertain

0.65

PROVEAN

Pathogenic

-5.9

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

REVEL

Pathogenic

0.88

Sift

Pathogenic

0.0

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

Sift4G

Uncertain

0.0020

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

Polyphen

1.0

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

Vest4

0.85

MutPred

0.62

Loss of disorder (P = 0.0026);Loss of disorder (P = 0.0026);Loss of disorder (P = 0.0026);Loss of disorder (P = 0.0026);.;.;.;.;

MVP

0.96

MPC

1.1

ClinPred

1.0

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.93

gMVP

0.95

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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

Other links and lift over