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).
ClinVar Genomic variation as it relates to human health
NM_170707.4(LMNA):c.481G>A (p.Glu161Lys)
Germline
Classification
Help
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.
(17)
Help
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
17
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.481G>A (p.Glu161Lys)
Variation ID: 14504 Accession: VCV000014504.62
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 1q22 1: 156130741 (GRCh38) [ NCBI UCSC ] 1: 156100532 (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 Apr 4, 2013 Dec 22, 2024 Oct 16, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_170707.4:c.481G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_733821.1:p.Glu161Lys missense NM_005572.4:c.481G>A MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_005563.1:p.Glu161Lys missense NM_001257374.3:c.145G>A NP_001244303.1:p.Glu49Lys missense NM_001282624.2:c.238G>A NP_001269553.1:p.Glu80Lys missense NM_001282625.2:c.481G>A NP_001269554.1:p.Glu161Lys missense NM_001282626.2:c.481G>A NP_001269555.1:p.Glu161Lys missense NM_170708.4:c.481G>A NP_733822.1:p.Glu161Lys missense NC_000001.11:g.156130741G>A NC_000001.10:g.156100532G>A NG_008692.2:g.53169G>A LRG_254:g.53169G>A LRG_254t2:c.481G>A P02545:p.Glu161Lys - Protein change
- E161K, E80K, E49K
- Other names
-
p.E161K:GAG>AAG
- Canonical SPDI
- NC_000001.11:156130740:G:A
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe 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
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 | ||
|---|---|---|---|---|---|---|
| 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 |
1883 | 2171 | |
| LOC126805877 | - | - | - | GRCh38 | - | 162 |
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. |
|---|---|---|---|---|
| Pathogenic (4) |
criteria provided, single submitter
|
Feb 8, 2013 | RCV000015598.35 | |
| Pathogenic (2) |
criteria provided, single submitter
|
Apr 10, 2023 | RCV000211788.9 | |
| Pathogenic/Likely pathogenic (7) |
criteria provided, multiple submitters, no conflicts
|
Oct 16, 2024 | RCV000057409.39 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Sep 15, 2023 | RCV000687241.10 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Apr 30, 2021 | RCV001170451.5 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jan 8, 2024 | RCV003318333.3 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Dec 19, 2023 | RCV004018635.1 |
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. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Sep 15, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Charcot-Marie-Tooth disease type 2
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000814798.7
First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024 |
Comment:
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). … (more)
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). (less)
|
|
|
Pathogenic
(Feb 08, 2013)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiomyopathy, dilated, 1A
Affected status: yes
Allele origin:
germline
|
Genetic Services Laboratory, University of Chicago
Accession: SCV000595617.1
First in ClinVar: May 29, 2016 Last updated: May 29, 2016 |
|
|
|
Pathogenic
(Apr 30, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiomyopathy
Affected status: unknown
Allele origin:
germline
|
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Accession: SCV001333031.2
First in ClinVar: May 31, 2020 Last updated: Dec 29, 2021 |
|
|
|
Pathogenic
(Jan 08, 2024)
|
criteria provided, single submitter
Method: research
|
Long QT syndrome
Affected status: yes
Allele origin:
paternal
|
Dept of Medical Biology, Uskudar University
Accession: SCV004021951.2
First in ClinVar: Jul 29, 2023 Last updated: Jan 26, 2024 |
Comment:
Criteria: PS4_Strong, PS3_Supporting, PM1, PM2, PP3
Number of individuals with the variant: 2
Sex: male
Ethnicity/Population group: Turkish
Geographic origin: Turkey
|
|
|
Pathogenic
(Apr 10, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Primary dilated cardiomyopathy
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
All of Us Research Program, National Institutes of Health
Accession: SCV004822972.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024
Comment:
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more)
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)
|
Comment:
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 … (more)
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. (less)
Number of individuals with the variant: 1
Zygosity: Single Heterozygote
|
|
|
Pathogenic
(Dec 19, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV005030794.1
First in ClinVar: May 01, 2024 Last updated: May 01, 2024 |
Comment:
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 … (more)
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. (less)
|
|
|
Pathogenic
(Oct 16, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000234736.14
First in ClinVar: Jul 05, 2015 Last updated: Oct 26, 2024 |
Comment:
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 … (more)
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) (less)
|
|
|
Likely pathogenic
(Nov 01, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV000574794.33
First in ClinVar: Mar 08, 2017 Last updated: Dec 22, 2024 |
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Aug 01, 2003)
|
no assertion criteria provided
Method: literature only
|
CARDIOMYOPATHY, DILATED, 1A
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000035863.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
Sebillon et al. (2003) described a family with a history of sudden cardiac death, congestive heart failure, and dilated cardiomyopathy (CMD1A; 115200). Five affected members … (more)
Sebillon et al. (2003) described a family with a history of sudden cardiac death, congestive heart failure, and dilated cardiomyopathy (CMD1A; 115200). Five affected members had a heterozygous 481G-A transition in exon 2 of the LMNA gene, resulting in a glu161-to-lys (E161K) mutation. Dilated cardiomyopathy was present in only 2 patients, in whom onset of the disease was characterized by congestive heart failure and atrial fibrillation (at 29 and 44 years, respectively); heart transplantation was performed in both patients (at 34 and 51 years of age). In the 3 other affected members, the onset of disease was also characterized by atrial fibrillation at 22, 49, and 63 years, but without dilated cardiomyopathy. A 16-year-old male and 12-year-old female were also heterozygous for the mutation, but had no signs or symptoms of heart disease. The 5 affected members were a mother and 2 daughters in 1 branch of the family and 2 brothers in another branch. Two cardiac deaths were reported in the family history: sudden death at 38 years and congestive heart failure at 68 years. No significant atrioventricular block was observed in the family, except in 1 patient for whom cardiac pacing was necessary at 67 years of age because of sinoatrial block coexisting with atrial fibrillation. Sebillon et al. (2003) concluded that the phenotype in this family was characterized by early atrial fibrillation preceding or coexisting with dilated cardiomyopathy, without significant atrioventricular block, and without neuromuscular abnormalities. (less)
|
|
|
Pathogenic
(Jun 26, 2009)
|
no assertion criteria provided
Method: clinical testing
|
Primary dilated cardiomyopathy
Affected status: not provided
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000065044.4
First in ClinVar: May 03, 2013 Last updated: Jun 01, 2016 |
Number of individuals with the variant: 2
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001964197.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021 |
|
|
|
Pathogenic
(Apr 27, 2021)
|
no assertion criteria provided
Method: clinical testing
|
CARDIOMYOPATHY, DILATED, 1A
Affected status: yes
Allele origin:
germline
|
Sangiuolo Lab - Medical Genetics Laboratory, Tor Vergata University
Accession: SCV001593103.1
First in ClinVar: Nov 11, 2021 Last updated: Nov 11, 2021 |
Number of individuals with the variant: 1
|
|
|
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: SCV001743140.3 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: SCV001952305.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Genome Diagnostics Laboratory, University Medical Center Utrecht
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV002033947.1 First in ClinVar: Dec 18, 2021 Last updated: Dec 18, 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: SCV000088522.1
First in ClinVar: Oct 19, 2013 Last updated: Oct 19, 2013 |
|
|
|
not provided
(-)
|
no classification provided
Method: phenotyping only
|
Dilated cardiomyopathy 1A
Affected status: unknown
Allele origin:
germline
|
GenomeConnect, ClinGen
Accession: SCV000986874.1
First in ClinVar: Aug 30, 2019 Last updated: Aug 30, 2019 |
Comment:
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 … (more)
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. (less)
Clinical Features:
Myopia (present) , Anxiety (present) , Arrhythmia (present) , Periodontitis (present) , Misalignment of teeth (present)
Age: 30-39 years
Sex: female
Testing laboratory: GeneDx
Date variant was reported to submitter: 2012-05-23
Testing laboratory interpretation: Pathogenic
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Comment:
Comment:
Criteria: PS4_Strong, PS3_Supporting, PM1, PM2, PP3
Comment:
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.
Comment:
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.
Comment:
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)
Comment:
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.
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
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).
Comment:
Criteria: PS4_Strong, PS3_Supporting, PM1, PM2, PP3
Comment:
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.
Comment:
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.
Comment:
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)
Comment:
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.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Personalized Medicine Approach in a DCM Patient with LMNA Mutation Reveals Dysregulation of mTOR Signaling. | Neupane B | Journal of personalized medicine | 2022 | PMID: 35887646 |
| Clinical Features of LMNA-Related Cardiomyopathy in 18 Patients and Characterization of Two Novel Variants. | Ferradini V | Journal of clinical medicine | 2021 | PMID: 34768595 |
| Implications of Genetic Testing in Dilated Cardiomyopathy. | Verdonschot JAJ | Circulation. Genomic and precision medicine | 2020 | PMID: 32880476 |
| Viscoelastic behavior of cardiomyocytes carrying LMNA mutations. | Borin D | Biorheology | 2020 | PMID: 32083564 |
| Altered microtubule structure, hemichannel localization and beating activity in cardiomyocytes expressing pathologic nuclear lamin A/C. | Borin D | Heliyon | 2020 | PMID: 32021920 |
| Genetic Risk of Arrhythmic Phenotypes in Patients With Dilated Cardiomyopathy. | Gigli M | Journal of the American College of Cardiology | 2019 | PMID: 31514951 |
| Reevaluation of genetic variants previously associated with arrhythmogenic right ventricular cardiomyopathy integrating population-based cohorts and proteomics data. | Ye JZ | Clinical genetics | 2019 | PMID: 31402444 |
| Biomechanical defects and rescue of cardiomyocytes expressing pathologic nuclear lamins. | Laurini E | Cardiovascular research | 2018 | PMID: 29432544 |
| Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples. | Walsh R | Genetics in medicine : official journal of the American College of Medical Genetics | 2017 | PMID: 27532257 |
| Viscoelastic behavior of human lamin A proteins in the context of dilated cardiomyopathy. | Banerjee A | PloS one | 2013 | PMID: 24386194 |
| Structural alterations of Lamin A protein in dilated cardiomyopathy. | Bhattacharjee P | Biochemistry | 2013 | PMID: 23701190 |
| Altered chromosomal positioning, compaction, and gene expression with a lamin A/C gene mutation. | Mewborn SK | PloS one | 2010 | PMID: 21179469 |
| Validation of high-resolution DNA melting analysis for mutation scanning of the LMNA gene. | Millat G | Clinical biochemistry | 2009 | PMID: 19318026 |
| Identification of mutational hot spots in LMNA encoding lamin A/C in patients with familial dilated cardiomyopathy. | Perrot A | Basic research in cardiology | 2009 | PMID: 18795223 |
| Long-term outcome and risk stratification in dilated cardiolaminopathies. | Pasotti M | Journal of the American College of Cardiology | 2008 | PMID: 18926329 |
| Lamin A/C mutations associated with familial and sporadic cases of dilated cardiomyopathy in Koreans. | Song K | Experimental & molecular medicine | 2007 | PMID: 17334235 |
| Expanding the phenotype of LMNA mutations in dilated cardiomyopathy and functional consequences of these mutations. | Sébillon P | Journal of medical genetics | 2003 | PMID: 12920062 |
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Record last updated Dec 22, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.