ClinVar Genomic variation as it relates to human health
NM_170707.4(LMNA):c.658C>T (p.Arg220Cys)
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.658C>T (p.Arg220Cys)
Variation ID: 264626 Accession: VCV000264626.37
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1q22 1: 156134823 (GRCh38) [ NCBI UCSC ] 1: 156104614 (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 3, 2016 Sep 29, 2024 Mar 29, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_170707.4:c.658C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_733821.1:p.Arg220Cys missense NM_005572.4:c.658C>T MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_005563.1:p.Arg220Cys missense NM_001257374.3:c.322C>T NP_001244303.1:p.Arg108Cys missense NM_001282624.2:c.415C>T NP_001269553.1:p.Arg139Cys missense NM_001282625.2:c.658C>T NP_001269554.1:p.Arg220Cys missense NM_001282626.2:c.658C>T NP_001269555.1:p.Arg220Cys missense NM_170708.4:c.658C>T NP_733822.1:p.Arg220Cys missense NC_000001.11:g.156134823C>T NC_000001.10:g.156104614C>T NG_008692.2:g.57251C>T LRG_254:g.57251C>T LRG_254t2:c.658C>T - Protein change
- R220C, R108C, R139C
- Other names
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- Canonical SPDI
- NC_000001.11:156134822:C:T
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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.
The Genome Aggregation Database (gnomAD) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00002
Exome Aggregation Consortium (ExAC) 0.00003
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
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 |
1835 | 2113 |
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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Uncertain significance (1) |
criteria provided, single submitter
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Mar 14, 2024 | RCV000247356.3 | |
Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
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Mar 29, 2024 | RCV000594818.22 | |
Uncertain significance (1) |
criteria provided, single submitter
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Nov 17, 2023 | RCV000800454.9 | |
Uncertain significance (1) |
criteria provided, single submitter
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May 17, 2023 | RCV001179387.4 | |
Uncertain significance (1) |
criteria provided, single submitter
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Nov 20, 2023 | RCV003995736.2 |
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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Uncertain significance
(Mar 14, 2024)
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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: SCV000320673.7
First in ClinVar: Oct 03, 2016 Last updated: May 01, 2024 |
Comment:
The p.R220C variant (also known as c.658C>T), located in coding exon 4 of the LMNA gene, results from a C to T substitution at nucleotide … (more)
The p.R220C variant (also known as c.658C>T), located in coding exon 4 of the LMNA gene, results from a C to T substitution at nucleotide position 658. The arginine at codon 220 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been reported in an individual with concerns for Emery-Dreifuss muscular dystrophy (Díaz-Manera J et al. Neuromuscul. Disord., 2016 Jan;26:33-40). This variant has also been detected in individuals indicated as having dilated cardiomyopathy or cardiac conduction system disease; however, clinical details were limited (Park J et al. Genet Med. 2020 Jan;22(1):102-111; Verdonschot JAJ et al. Circ Genom Precis Med, 2020 Oct;13:476-487; Bourfiss M et al. Circ Genom Precis Med, 2022 Dec;15:e003704). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
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Uncertain significance
(Dec 28, 2016)
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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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Eurofins Ntd Llc (ga)
Accession: SCV000704256.2
First in ClinVar: Apr 02, 2018 Last updated: Apr 02, 2018 |
Number of individuals with the variant: 1
Sex: mixed
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Uncertain significance
(Nov 17, 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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000940169.6
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 220 of the LMNA protein … (more)
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 220 of the LMNA protein (p.Arg220Cys). This variant is present in population databases (rs370134870, gnomAD 0.004%). This missense change has been observed in individual(s) with LMNA-related conditions (PMID: 26573435, 31383942, 32880476). ClinVar contains an entry for this variant (Variation ID: 264626). 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%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
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Uncertain significance
(May 17, 2023)
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criteria provided, single submitter
Method: clinical testing
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Cardiomyopathy
Affected status: unknown
Allele origin:
germline
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Color Diagnostics, LLC DBA Color Health
Accession: SCV001344041.3
First in ClinVar: Jun 22, 2020 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces arginine with cysteine at codon 220 of the LMNA protein. Computational prediction is inconclusive regarding the impact of this variant on … (more)
This missense variant replaces arginine with cysteine at codon 220 of the LMNA protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with dilated cardiomyopathy (PMID: 32880476) and in individuals affected with cardiomyopathy and conduction defects (PMID: 31383942). It has also been reported in two unrelated individuals affected with Emery-Dreifuss muscular dystrophy (PMID: 26573435, DOI:10.1016/j.nmd.2007.06.126). The variant was in homozygous state in one of the two individuals, and the unaffected parents were both heterozygous carriers (DOI:10.1016/j.nmd.2007.06.126). This variant has also been reported in an individual from a cohort of participants undergoing whole exome sequencing in clinical research studies (PMID: 30122538). This variant has been identified in 6/251360 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
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Uncertain Significance
(Nov 20, 2023)
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criteria provided, single submitter
Method: clinical testing
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Primary dilated cardiomyopathy
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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All of Us Research Program, National Institutes of Health
Accession: SCV004845513.1
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)
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Comment:
This missense variant replaces arginine with cysteine at codon 220 of the LMNA protein. Computational prediction is inconclusive regarding the impact of this variant on … (more)
This missense variant replaces arginine with cysteine at codon 220 of the LMNA protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with dilated cardiomyopathy (PMID: 32880476) and in individuals affected with cardiomyopathy and conduction defects (PMID: 31383942). It has also been reported in two unrelated individuals affected with Emery-Dreifuss muscular dystrophy (PMID: 26573435, DOI:10.1016/j.nmd.2007.06.126). The variant was in homozygous state in one of the two individuals, and the unaffected parents were both heterozygous carriers (DOI:10.1016/j.nmd.2007.06.126). This variant has also been reported in an individual from a cohort of participants undergoing whole exome sequencing in clinical research studies (PMID: 30122538). This variant has been identified in 6/251360 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
Number of individuals with the variant: 4
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Uncertain significance
(Apr 01, 2023)
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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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV004124987.8
First in ClinVar: Nov 20, 2023 Last updated: Aug 04, 2024 |
Comment:
LMNA: PM2:Supporting, PM5:Supporting, PP3
Number of individuals with the variant: 1
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Uncertain significance
(Mar 29, 2024)
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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: SCV001777600.6
First in ClinVar: Aug 13, 2021 Last updated: Sep 29, 2024 |
Comment:
Reported in the homozygous state in a patient with childhood-onset muscle weakness, contractures, and adult-onset dilated cardiomyopathy in published literature (PMID: 26573435); Not observed at … (more)
Reported in the homozygous state in a patient with childhood-onset muscle weakness, contractures, and adult-onset dilated cardiomyopathy in published literature (PMID: 26573435); 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; This variant is associated with the following publications: (PMID: 28663758, 32155092, 32880476, 35011612, 30564623, 31383942, 10939567, 26573435, 30122538, 36264615) (less)
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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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Prevalence and Disease Expression of Pathogenic and Likely Pathogenic Variants Associated With Inherited Cardiomyopathies in the General Population. | Bourfiss M | Circulation. Genomic and precision medicine | 2022 | PMID: 36264615 |
Implications of Genetic Testing in Dilated Cardiomyopathy. | Verdonschot JAJ | Circulation. Genomic and precision medicine | 2020 | PMID: 32880476 |
A genome-first approach to aggregating rare genetic variants in LMNA for association with electronic health record phenotypes. | Park J | Genetics in medicine : official journal of the American College of Medical Genetics | 2020 | PMID: 31383942 |
Evaluation of Recipients of Positive and Negative Secondary Findings Evaluations in a Hybrid CLIA-Research Sequencing Pilot. | Sapp JC | American journal of human genetics | 2018 | PMID: 30122538 |
Muscle imaging in muscle dystrophies produced by mutations in the EMD and LMNA genes. | Díaz-Manera J | Neuromuscular disorders : NMD | 2016 | PMID: 26573435 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=LMNA | - | - | - | - |
Text-mined citations for rs370134870 ...
HelpRecord last updated Sep 29, 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.