rs28933093
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2PP2PP3_StrongPP5_Very_Strong
The NM_170707.4(LMNA):c.481G>A(p.Glu161Lys) variant causes a missense change involving the alteration of a 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 (★★). Synonymous variant affecting the same amino acid position (i.e. E161E) has been classified as Likely benign.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
LMNA
NM_170707.4 missense
NM_170707.4 missense
Scores
13
5
2
Clinical Significance
Conservation
PhyloP100: 10.0
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 17 ACMG points.
PM1
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_170707.4
PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), LMNA. . Gene score misZ: 2.3673 (greater than the threshold 3.09). Trascript score misZ: 3.0905 (greater than threshold 3.09). The gene has 178 curated pathogenic missense variants (we use a threshold of 10). The gene has 69 curated benign missense variants. GenCC has associacion of the gene with 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, 0.978
PP5
Variant 1-156130741-G-A is Pathogenic according to our data. Variant chr1-156130741-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 14504.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-156130741-G-A is described in Lovd as [Pathogenic]. Variant chr1-156130741-G-A is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| LMNA | NM_170707.4 | c.481G>A | p.Glu161Lys | missense_variant | 2/12 | ENST00000368300.9 | NP_733821.1 | |
| LMNA | NM_005572.4 | c.481G>A | p.Glu161Lys | missense_variant | 2/10 | ENST00000677389.1 | NP_005563.1 |
Ensembl
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1451192Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 721142
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
AC:
0
AN:
1451192
Hom.:
Cov.:
32
AF XY:
AC XY:
0
AN XY:
721142
Gnomad4 AFR exome
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GnomAD4 genome
GnomAD4 genome
Cov.:
32
Alfa
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:15Other:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:6Other:1
| Pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Nov 01, 2016 | - - |
| not provided, no classification provided | literature only | Epithelial Biology; Institute of Medical Biology, Singapore | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 16, 2024 | Observed in individuals with dilated cardiomyopathy and segregates with disease in multiple individuals from several families (PMID: 12920062, 17334235, 18795223, 24503780, 21846512); Identified in a family with two reported cardiac deaths; seven living family members were heterozygous for this variant, two of whom had DCM with atrial fibrillation and congestive heart failure necessitating heart transplantation, three others had only atrial fibrillation, and two younger individuals were asymptomatic (PMID: 12920062); Not observed at significant frequency in large population cohorts (gnomAD); Functional studies of p.(E161K) in mutant heart and fibroblasts showed that this variant is likely to disrupt normal gene expression due to alteration in the nuclear positioning of chromosomes (PMID: 21179469, 21818408); Additional functional studies in vitro have shown that p.(E161K) results in alteration of protein secondary and tertiary structure with improper oligomerization suggesting that this variant alters mechanotransduction in cardiomyocytes (PMID: 23701190, 24386194); 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: 34768595, 30178466, 30287275, 34862408, 18926329, 24503780, 21818408, 23701190, 26199943, 17334235, 18795223, 21846512, 27532257, 27301336, 28679633, 29432544, 28844980, 31402444, 31737537, 31383942, 32021920, 31744510, 31514951, 30420677, 32880476, 24386194, 36548481, 10939567, 36396199, 21179469, 12920062, 37652022, 35887646, 37728764) - |
| Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Dilated cardiomyopathy 1A Pathogenic:3Other:1
| Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Feb 08, 2013 | - - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Aug 01, 2003 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Sangiuolo Lab - Medical Genetics Laboratory, Tor Vergata University | Apr 27, 2021 | - - |
| not provided, no classification provided | phenotyping only | GenomeConnect, ClinGen | - | Variant interpretted as pathogenic and reported on 05/23/2012 by GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. - |
Primary dilated cardiomyopathy Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Apr 10, 2023 | This missense variant replaces glutamic acid with lysine at codon 161 in the intermediate filament rod domain of the LMNA protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies in mouse embryonic stem cells have shown that this variant causes increased nuclear blebbing and decreased nuclear lamin organization; additional functional studies have shown that this variant causes changes in the secondary and tertiary structure of the LMNA protein as well as abnormal gene expression profiles (PMID: 21179469, 23701190, 32083564, 35887646). This variant has been reported in individuals affected with dilated cardiomyopathy (PMID: 12920062, 17334235, 18795223, 18926329, 19318026, 21179469, 27532257, 34768595, 35887646, 35887646). It has been shown that this variant segregates with disease in multiple affected individuals across two families (PMID: 18926329, 35887646). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. - |
| Pathogenic, no assertion criteria provided | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jun 26, 2009 | - - |
Cardiomyopathy Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Apr 30, 2021 | - - |
Charcot-Marie-Tooth disease type 2 Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Sep 15, 2023 | For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects LMNA function (PMID: 23701190, 24386194, 29432544). 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. ClinVar contains an entry for this variant (Variation ID: 14504). This missense change has been observed in individual(s) with dilated cardiomyopathy (DCM) (PMID: 12920062, 18795223, 19318026, 27532257, 29432544). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 161 of the LMNA protein (p.Glu161Lys). - |
Long QT syndrome Pathogenic:1
| Pathogenic, criteria provided, single submitter | research | Dept of Medical Biology, Uskudar University | Jan 08, 2024 | Criteria: PS4_Strong, PS3_Supporting, PM1, PM2, PP3 - |
Cardiovascular phenotype Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 19, 2023 | The p.E161K pathogenic mutation (also known as c.481G>A), located in coding exon 2 of the LMNA gene, results from a G to A substitution at nucleotide position 481. The glutamic acid at codon 161 is replaced by lysine, an amino acid with similar properties. This alteration has been reported in probands with a history of LMNA-related disease (Pasotti M et al. J Am Coll Cardiol, 2008 Oct;52:1250-60; Perrot A et al. Basic Res Cardiol, 2009 Jan;104:90-9; Walsh R et al. Genet Med, 2017 Feb;19:192-203; Gigli M et al. J Am Coll Cardiol, 2019 Sep;74:1480-1490; Ferradini V et al. J Clin Med, 2021 Oct;10:; Ambry internal data). In addition, studies show this variant has an impact on protein function (Bhattacharjee P et al. Biochemistry, 2013 Jun;52:4229-41; Laurini E et al. Cardiovasc Res, 2018 May;114:846-857). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
CardioboostCm
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Pathogenic
.;.;.;D;.;.;.;D;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
T;D;D;T;T;T;T;D;T
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
H;.;H;H;H;.;.;.;.
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D;D;D;D;D;D;D;D
REVEL
Pathogenic
Sift
Uncertain
D;D;D;D;D;D;D;D;D
Sift4G
Uncertain
T;T;D;T;T;D;D;T;D
Polyphen
P;.;P;P;.;.;D;.;.
Vest4
MutPred
Gain of MoRF binding (P = 0.0095);Gain of MoRF binding (P = 0.0095);Gain of MoRF binding (P = 0.0095);Gain of MoRF binding (P = 0.0095);Gain of MoRF binding (P = 0.0095);.;.;.;.;
MVP
MPC
1.6
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at