ClinVar Genomic variation as it relates to human health
NM_170707.4(LMNA):c.244G>A (p.Glu82Lys)
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_170707.4(LMNA):c.244G>A (p.Glu82Lys)
Variation ID: 66882 Accession: VCV000066882.13
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1q22 1: 156115162 (GRCh38) [ NCBI UCSC ] 1: 156084953 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Oct 20, 2013 Feb 28, 2024 May 27, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_170707.4:c.244G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_733821.1:p.Glu82Lys missense NM_005572.4:c.244G>A MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_005563.1:p.Glu82Lys missense NM_001282625.2:c.244G>A NP_001269554.1:p.Glu82Lys missense NM_001282626.2:c.244G>A NP_001269555.1:p.Glu82Lys missense NM_170708.4:c.244G>A NP_733822.1:p.Glu82Lys missense NC_000001.11:g.156115162G>A NC_000001.10:g.156084953G>A NG_008692.2:g.37590G>A LRG_254:g.37590G>A LRG_254t2:c.244G>A - Protein change
- E82K
- Other names
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- Canonical SPDI
- NC_000001.11:156115161:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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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.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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. |
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LMNA | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
1751 | 2024 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (2) |
criteria provided, single submitter
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Mar 30, 2015 | RCV000057380.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Sep 6, 2013 | RCV000156060.4 | |
Pathogenic (1) |
criteria provided, single submitter
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May 27, 2023 | RCV000457442.10 |
Submissions - Germline
Classification
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The submitted germline classification for each SCV record. (Last evaluated) |
Review status
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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
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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
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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
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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. |
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Pathogenic
(Sep 06, 2013)
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criteria provided, single submitter
Method: clinical testing
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Primary dilated cardiomyopathy
(Autosomal dominant inheritance)
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000205773.4
First in ClinVar: Jan 31, 2015 Last updated: Jan 31, 2015 |
Comment:
The Glu82Lys variant in LMNA has been reported in at least 2 families with DCM a nd conduction system abnormalities, and segregated with disease in … (more)
The Glu82Lys variant in LMNA has been reported in at least 2 families with DCM a nd conduction system abnormalities, and segregated with disease in 8 affected re latives (Wang 2006, Wu 2010). It has not been identified in large population stu dies. Functional studies (in vitro) suggest an effect on protein function and mi ce carrying the variant exhibited clinical features of DCM (Wang 2006, Lu 2010, Sun 2010). In summary, this variant meets our criteria to be classified as patho genic (http://pcpgm.partners.org/LMM) based upon segregation studies, absence fr om controls, and functional evidence. (less)
Number of individuals with the variant: 1
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Pathogenic
(May 27, 2023)
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criteria provided, single submitter
Method: clinical testing
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Charcot-Marie-Tooth disease type 2
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000548860.8
First in ClinVar: Apr 17, 2017 Last updated: Feb 28, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects LMNA function (PMID: 20497714, 21151901). Advanced … (more)
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects LMNA function (PMID: 20497714, 21151901). 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: 66882). This missense change has been observed in individual(s) with dilated cardiomyopathy (DCM) and atrioventricular (AV) block (PMID: 16630578, 20155465). 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 82 of the LMNA protein (p.Glu82Lys). (less)
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Pathogenic
(Mar 30, 2015)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000292778.10
First in ClinVar: Oct 20, 2013 Last updated: Oct 20, 2013 |
Comment:
The E82K mutation was reported to segregate with DCM and atrial ventricular block in eight individuals from two Chinese families (Wang et al., 2006; Wu … (more)
The E82K mutation was reported to segregate with DCM and atrial ventricular block in eight individuals from two Chinese families (Wang et al., 2006; Wu et al., 2010). E82K was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In vitro studies showed E82K significantly reduced expression and altered localization of connexin 43 (Sun et al., 2010). Studies in transgenic mice showed E82K activates the FAS and mitochondrial pathways of apoptosis in heart tissue (Lu et al., 2010). E82K is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense mutations in nearby residues (R72L, R72C, L85R, R89L) have been reported in the Human Gene Mutation Database in association with cardiomyopathy (Stenson et al., 2014), supporting the functional importance of this region of the protein. (less)
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not provided
(-)
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no classification provided
Method: not provided
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not provided
Affected status: not provided
Allele origin:
not provided
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Epithelial Biology; Institute of Medical Biology, Singapore
Accession: SCV000088493.1
First in ClinVar: Oct 20, 2013 Last updated: Oct 20, 2013 |
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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LMNA E82K mutation activates FAS and mitochondrial pathways of apoptosis in heart tissue specific transgenic mice. | Lu D | PloS one | 2010 | PMID: 21151901 |
Connexin 43 remodeling induced by LMNA gene mutation Glu82Lys in familial dilated cardiomyopathy with atrial ventricular block. | Sun LP | Chinese medical journal | 2010 | PMID: 20497714 |
Identification of a new lamin A/C mutation in a Chinese family affected with atrioventricular block as the prominent phenotype. | Wu X | Journal of Huazhong University of Science and Technology. Medical sciences = Hua zhong ke ji da xue xue bao. Yi xue Ying De wen ban = Huazhong keji daxue xuebao. Yixue Yingdewen ban | 2010 | PMID: 20155465 |
[Effects of a novel familial dilated cardiomyopathy associated LMNA gene mutation E82K on cell cycle of HEK293 cells]. | Wang H | Zhonghua xin xue guan bing za zhi | 2007 | PMID: 17386158 |
Mutation Glu82Lys in lamin A/C gene is associated with cardiomyopathy and conduction defect. | Wang H | Biochemical and biophysical research communications | 2006 | PMID: 16630578 |
[A novel LMNA gene mutation E82K associated with familial dilated cardiomyopathy]. | Wang H | Zhonghua xin xue guan bing za zhi | 2005 | PMID: 16266469 |
Text-mined citations for rs59270054 ...
HelpRecord last updated Apr 06, 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.