ClinVar Genomic variation as it relates to human health
NM_170707.4(LMNA):c.607G>A (p.Glu203Lys)
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.607G>A (p.Glu203Lys)
Variation ID: 48070 Accession: VCV000048070.29
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1q22 1: 156134496 (GRCh38) [ NCBI UCSC ] 1: 156104287 (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 1, 2013 Jun 17, 2024 Dec 12, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_170707.4:c.607G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_733821.1:p.Glu203Lys missense NM_005572.4:c.607G>A MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_005563.1:p.Glu203Lys missense NM_001257374.3:c.271G>A NP_001244303.1:p.Glu91Lys missense NM_001282624.2:c.364G>A NP_001269553.1:p.Glu122Lys missense NM_001282625.2:c.607G>A NP_001269554.1:p.Glu203Lys missense NM_001282626.2:c.607G>A NP_001269555.1:p.Glu203Lys missense NM_170708.4:c.607G>A NP_733822.1:p.Glu203Lys missense NC_000001.11:g.156134496G>A NC_000001.10:g.156104287G>A NG_008692.2:g.56924G>A LRG_254:g.56924G>A LRG_254t2:c.607G>A P02545:p.Glu203Lys - Protein change
- E203K, E91K, E122K
- Other names
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- Canonical SPDI
- NC_000001.11:156134495: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 |
1826 | 2104 |
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
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
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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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not provided (1) |
no classification provided
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- | RCV000055999.5 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Dec 22, 2021 | RCV000057427.12 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Feb 20, 2018 | RCV000211790.5 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 16, 2023 | RCV000618699.3 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 12, 2023 | RCV000653912.9 | |
not provided (1) |
no classification provided
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- | RCV001824588.2 |
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
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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
(Oct 16, 2023)
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criteria provided, single submitter
Method: clinical testing
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Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV000737218.5
First in ClinVar: Apr 14, 2018 Last updated: May 01, 2024 |
Comment:
The p.E203K pathogenic mutation (also known as c.607G>A), located in coding exon 3 of the LMNA gene, results from a G to A substitution at … (more)
The p.E203K pathogenic mutation (also known as c.607G>A), located in coding exon 3 of the LMNA gene, results from a G to A substitution at nucleotide position 607. The glutamic acid at codon 203 is replaced by lysine, an amino acid with similar properties. This variant has been reported in multiple unrelated individuals with dilated cardiomyopathy (DCM) and/or conduction system disease and has been shown to segregate with disease phenotype in one large family (Jakobs PM et al. J. Card. Fail. 2001;7:249-56; Lakdawala NK et al. J. Card. Fail. 2012;18:296-303). In addition, functional studies have demonstrated deficient LMNA protein function both in cell lines expressing E203K and in fibroblasts from patients heterozygous for this mutation (Zhang YQ et al. J. Cell Biol. 2008;182:35-9; Cowan J et al. Circ Cardiovasc Genet. 2010;3:6-14). 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)
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Pathogenic
(Dec 12, 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: SCV000775802.7
First in ClinVar: May 28, 2018 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 203 of the LMNA protein … (more)
This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 203 of the LMNA protein (p.Glu203Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant LMNA-related conditions (PMID: 11561226, 22464770). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 48070). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects LMNA function (PMID: 18606848, 20160190). This variant disrupts the p.Glu203 amino acid residue in LMNA. Other variant(s) that disrupt this residue have been observed in individuals with LMNA-related conditions (PMID: 10580070, 18795223), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. (less)
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Likely pathogenic
(Feb 20, 2018)
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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: SCV000065048.5
First in ClinVar: May 03, 2013 Last updated: Apr 09, 2018 |
Comment:
The p.Glu203Lys variant in LMNA has been reported in 2 individuals with dilated cardiomyopathy, and in one family segregated with DCM in two individuals and … (more)
The p.Glu203Lys variant in LMNA has been reported in 2 individuals with dilated cardiomyopathy, and in one family segregated with DCM in two individuals and con duction system disease in another 6 individuals (Jakobs 2001, LMM data). It was also absent from large population studies. This variant has been reported in Cli nVar (Variation ID: 48070). In vitro functional studies provide some evidence th at the p.Glu203Lys variant may impact protein function (Cowan 2010), while anoth er had inconclusive findings (Zwerger 2013). However, these types of assays may not accurately represent biological function. Finally, another missense variant at this position has been reported to segregate with DCM (p.Glu203Gly; Fatkin 19 99). In summary, although additional studies are required to fully establish its clinical significance, the p.Glu203Lys variant is likely pathogenic for dilated cardiomyopathy in an autosomal dominant manner. ACMG/AMP Criteria applied: PP1_ Strong, PM2, PS3_Supporting, PS4_Supporting. (less)
Number of individuals with the variant: 2
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Pathogenic
(Dec 22, 2021)
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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: SCV000293035.13
First in ClinVar: Oct 19, 2013 Last updated: Mar 04, 2023 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; … (more)
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Functional studies suggest that the E203K variant disrupts lamin A localization, resulting in protein aggregation and increased cell death (Zhang et al., 2008; Cowen et al., 2010); Reported in ClinVar (ClinVar Variant ID# 48070; ClinVar); This variant is associated with the following publications: (PMID: 29764566, 10580070, 23427149, 18606848, 23582089, 18585512, 18795223, 22464770, 27374873, 11561226, 30934932, 31514951, 31983221, 32455078, 32719615, 32471220, 20160190, 26199943, 20301717, 24556839, 23475188, 22886719, 21639948, 20079693, 19282183, 10939567) (less)
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Pathogenic
(May 20, 2021)
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criteria provided, single submitter
Method: clinical testing
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Not provided
Affected status: unknown
Allele origin:
germline
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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV001715326.2
First in ClinVar: Jun 15, 2021 Last updated: Jun 03, 2023 |
Comment:
PS3, PM1, PM2, PM5, PP1_strong, PP3
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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: SCV000088541.1
First in ClinVar: Oct 19, 2013 Last updated: Oct 19, 2013 |
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not provided
(-)
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no classification provided
Method: literature only
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Dilated cardiomyopathy 1A
Affected status: not provided
Allele origin:
unknown
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GeneReviews
Accession: SCV000087055.2
First in ClinVar: Oct 01, 2013 Last updated: Oct 01, 2022 |
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not provided
(-)
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no classification provided
Method: phenotyping only
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Emery-Dreifuss muscular dystrophy 2, autosomal dominant
Emery-Dreifuss muscular dystrophy 3, autosomal recessive Dilated cardiomyopathy 1A Congenital muscular dystrophy due to LMNA mutation Charcot-Marie-Tooth disease type 2B1 Familial partial lipodystrophy, Dunnigan type Mandibuloacral dysplasia with type A lipodystrophy Hutchinson-Gilford syndrome
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.
Affected status: unknown
Allele origin:
unknown
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GenomeConnect, ClinGen
Accession: SCV002074884.2
First in ClinVar: Feb 12, 2022 Last updated: Jun 17, 2024 |
Comment:
Variant interpreted as Pathogenic and reported on 07-09-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided … (more)
Variant interpreted as Pathogenic and reported on 07-09-2020 by Lab or GTR ID 500031. 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:
Cardiac arrhythmia (present) , Abnormal EKG (present) , Abnormality of the cardiovascular system (present) , Asthma (present) , Tooth malposition (present)
Indication for testing: Diagnostic, Family Testing
Age: 30-39 years
Sex: female
Testing laboratory: Invitae
Date variant was reported to submitter: 2020-07-09
Testing laboratory interpretation: Pathogenic
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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-Related Dilated Cardiomyopathy. | Adam MP | - | 2022 | PMID: 20301717 |
Lamin A/C Cardiomyopathy with E203K Pathogenic Mutation. | Sheikh FN | Cureus | 2020 | PMID: 32455078 |
Reevaluating the Genetic Contribution of Monogenic Dilated Cardiomyopathy. | Mazzarotto F | Circulation | 2020 | PMID: 31983221 |
Genetic Risk of Arrhythmic Phenotypes in Patients With Dilated Cardiomyopathy. | Gigli M | Journal of the American College of Cardiology | 2019 | PMID: 31514951 |
Hutchinson-Gilford Progeria Syndrome: A premature aging disease caused by LMNA gene mutations. | Gonzalo S | Ageing research reviews | 2017 | PMID: 27374873 |
Temporal relationship of conduction system disease and ventricular dysfunction in LMNA cardiomyopathy. | Brodt C | Journal of cardiac failure | 2013 | PMID: 23582089 |
Myopathic lamin mutations impair nuclear stability in cells and tissue and disrupt nucleo-cytoskeletal coupling. | Zwerger M | Human molecular genetics | 2013 | PMID: 23427149 |
Genetic testing for dilated cardiomyopathy in clinical practice. | Lakdawala NK | Journal of cardiac failure | 2012 | PMID: 22464770 |
Morphological analysis of 13 LMNA variants identified in a cohort of 324 unrelated patients with idiopathic or familial dilated cardiomyopathy. | Cowan J | Circulation. Cardiovascular genetics | 2010 | PMID: 20160190 |
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 |
Sumoylation regulates lamin A function and is lost in lamin A mutants associated with familial cardiomyopathies. | Zhang YQ | The Journal of cell biology | 2008 | PMID: 18606848 |
Lamin A/C mutation analysis in a cohort of 324 unrelated patients with idiopathic or familial dilated cardiomyopathy. | Parks SB | American heart journal | 2008 | PMID: 18585512 |
Novel lamin A/C mutations in two families with dilated cardiomyopathy and conduction system disease. | Jakobs PM | Journal of cardiac failure | 2001 | PMID: 11561226 |
Missense mutations in the rod domain of the lamin A/C gene as causes of dilated cardiomyopathy and conduction-system disease. | Fatkin D | The New England journal of medicine | 1999 | PMID: 10580070 |
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Text-mined citations for rs61195471 ...
HelpRecord last updated Jun 17, 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.