ClinVar Genomic variation as it relates to human health
NM_170707.4(LMNA):c.568C>T (p.Arg190Trp)
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.568C>T (p.Arg190Trp)
Variation ID: 66908 Accession: VCV000066908.37
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1q22 1: 156134457 (GRCh38) [ NCBI UCSC ] 1: 156104248 (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 May 12, 2024 Jan 12, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_170707.4:c.568C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_733821.1:p.Arg190Trp missense NM_005572.4:c.568C>T MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_005563.1:p.Arg190Trp missense NM_001257374.3:c.232C>T NP_001244303.1:p.Arg78Trp missense NM_001282624.2:c.325C>T NP_001269553.1:p.Arg109Trp missense NM_001282625.2:c.568C>T NP_001269554.1:p.Arg190Trp missense NM_001282626.2:c.568C>T NP_001269555.1:p.Arg190Trp missense NM_170708.4:c.568C>T NP_733822.1:p.Arg190Trp missense NC_000001.11:g.156134457C>T NC_000001.10:g.156104248C>T NG_008692.2:g.56885C>T LRG_254:g.56885C>T LRG_254t2:c.568C>T P02545:p.Arg190Trp - Protein change
- R190W, R109W, R78W
- Other names
- p.R190W:CGG>TGG
- Canonical SPDI
- NC_000001.11:156134456: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
Help
The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00002
The Genome Aggregation Database (gnomAD) 0.00001
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
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. |
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LMNA | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
1818 | 2095 |
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. |
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Pathogenic (9) |
criteria provided, multiple submitters, no conflicts
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Nov 1, 2023 | RCV000057419.28 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 3, 2024 | RCV000535082.8 | |
Pathogenic (1) |
no assertion criteria provided
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May 1, 2016 | RCV000491585.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 15, 2023 | RCV000619878.5 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 12, 2024 | RCV003996512.2 | |
Pathogenic (1) |
criteria provided, single submitter
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May 27, 2023 | RCV004528262.1 |
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. |
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Pathogenic
(Jan 03, 2024)
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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: SCV000657816.8
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 190 of the LMNA protein … (more)
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 190 of the LMNA protein (p.Arg190Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 11897440, 15219508, 16061563, 16537768, 22199124, 26199943). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 66908). 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: 23701190, 24386194). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Dec 27, 2017)
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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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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000885657.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
Comment:
The LMNA c.568C>T; p.Arg190Trp variant (rs59026483) has been reported in several individuals with dilated cardiomyopathy and shown to segregate with disease in multiple families (Arbustini … (more)
The LMNA c.568C>T; p.Arg190Trp variant (rs59026483) has been reported in several individuals with dilated cardiomyopathy and shown to segregate with disease in multiple families (Arbustini 2002, Hermida-Prieto 2003, Karkkainen 2006, Pethig 2005, Song 2007, Sylvius 2005, Quarta 2012, see UMD-LMNA database). In addition, functional studies show the variant protein has altered viscoelastic properties, degrades more rapidly, and forms more protein aggregates compared to wild type protein (Banerjee 2013, Bhattacharjee 2013). This variant is reported as pathogenic in ClinVar (Variation ID: 66908), and is absent from the general population databases (1000 Genomes Project, Exome Variant Server, Genome Aggregation Database) indicating it is not a common polymorphism. The arginine at codon 190 is highly conserved and computational algorithms (SIFT, PolyPhen2, MutationTaster) predict this variant to be damaging to the protein. Based on the above information, the p.Arg190Trp variant is considered pathogenic. REFERENCES Link to UMD-LMNA database: http://www.umd.be/LMNA/ Arbustini E et al. Autosomal dominant dilated cardiomyopathy with atrioventricular block: a lamin A/C defect-related disease. J Am Coll Cardiol. 2002 Mar 20;39(6):981-90. Banerjee A et al. Viscoelastic behavior of human lamin A proteins in the context of dilated cardiomyopathy. PLoS One. 2013 Dec 30;8(12):e83410. Bhattacharjee P et al. Structural alterations of Lamin A protein in dilated cardiomyopathy. Biochemistry. 2013 Jun 18;52(24):4229-41. Hermida-Prieto M et al. Familial dilated cardiomyopathy and isolated left ventricular noncompaction associated with lamin A/C gene mutations. Am J Cardiol. 2004 Jul 1;94(1):50-4. Karkkainen S et al. Novel mutations in the lamin A/C gene in heart transplant recipients with end stage dilated cardiomyopathy. Heart. 2006 Apr;92(4):524-6. Pethig K et al. LMNA mutations in cardiac transplant recipients. Cardiology. 2005;103(2):57-62. Song K et al. Lamin A/C mutations associated with familial and sporadic cases of dilated cardiomyopathy in Koreans. Exp Mol Med. 2007 Feb 28;39(1):114-20. (less)
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Pathogenic
(Mar 03, 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: SCV000234674.11
First in ClinVar: Jul 05, 2015 Last updated: Apr 17, 2019 |
Comment:
Not observed in large population cohorts (Lek et al., 2016); Published functional studies demonstrate a damaging effect as this variant results in significant alterations in … (more)
Not observed in large population cohorts (Lek et al., 2016); Published functional studies demonstrate a damaging effect as this variant results in significant alterations in the secondary and tertiary structure of the protein, perturbing the protein's intrinsic self-association behavior (Banerjee at al., 2013; Bhattacharjee et al., 2013); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in ClinVar as a pathogenic variant (ClinVar Variant ID# 66908; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 20307303, 30420677, 31311496, 31317183, 23701190, 24386194, 20413395, 16061563, 25988045, 17729299, 22199124, 26899768, 26199943, 23328570, 16537768, 15219508, 23349452, 15539782, 17334235, 11897440, 28416588, 28679633, 29253866, 31028937, 31383942, 32041989, 31983221, 30847666, 31402444, 32880476) (less)
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Pathogenic
(May 27, 2023)
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criteria provided, single submitter
Method: clinical testing
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LMNA-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004106788.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The LMNA c.568C>T variant is predicted to result in the amino acid substitution p.Arg190Trp. This variant has been reported in many individuals with dilated cardiomyopathy … (more)
The LMNA c.568C>T variant is predicted to result in the amino acid substitution p.Arg190Trp. This variant has been reported in many individuals with dilated cardiomyopathy (Arbustini et al. 2002. PubMed ID: 11897440; Quarta et al. 2011. PubMed ID: 22199124; See Supp. Table 1 in Dal Ferro et al. 2017. PubMed ID: 28416588; See Dataset S5 in Ito et al. 2017. PubMed ID: 28679633). Functional studies indicate this variant alters protein structure and disrupts self-association of the lamin A protein (Bhattacharjee et al. 2013. PubMed ID: 23701190). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant has been reported in ClinVar by many outside laboratories as pathogenic (www.ncbi.nlm.nih.gov/clinvar/variation/66908). This variant is interpreted as pathogenic. (less)
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Pathogenic
(Jan 12, 2024)
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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: SCV004845015.1
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 tryptophan at codon 190 of the intermediate filament rod domain of the lamin A/C proteins. Computational prediction suggests that … (more)
This missense variant replaces arginine with tryptophan at codon 190 of the intermediate filament rod domain of the lamin A/C proteins. 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 have shown that this variant may disrupt the viscoelasticity of lamin A in the nuclear envelope (PMID: 23701190, 24386194). This variant has been reported in more than 10 unrelated individuals affected with dilated cardiomyopathy (PMID: 11897440, 15219508, 15539782, 16061563, 16537768, 17334235, 29947763, 23349452, 26199943, 26899768, 29947763, 32041989, 32880476; DOI 10.3390 Cuesta-Llavona 2022). It has also been reported in an individual affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 22199124). It has been shown that this variant segregates with disease in multiple affected individuals across multiple families (PMID: 11897440, 15219508, 15539782, 16061563, 17334235, 29947763, 26199943). A different variant occurring at the same codon, p.Arg190Gln, is a well documented pathogenic mutation (Clinvar variation ID: 66910), indicating that arginine at this position is important for LMNA protein function. 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: 2
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Pathogenic
(Nov 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: SCV003916511.8
First in ClinVar: Apr 23, 2023 Last updated: May 12, 2024 |
Comment:
LMNA: PM2, PM5, PP1:Moderate, PS4:Moderate, PP3, PS3:Supporting
Number of individuals with the variant: 4
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Pathogenic
(May 05, 2015)
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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: SCV000229074.5
First in ClinVar: Jun 28, 2015 Last updated: Mar 08, 2017 |
Number of individuals with the variant: 1
Sex: mixed
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Pathogenic
(Aug 15, 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: SCV000737299.6
First in ClinVar: Apr 14, 2018 Last updated: May 01, 2024 |
Comment:
The p.R190W pathogenic mutation (also known as c.568C>T), located in coding exon 3 of the LMNA gene, results from a C to T substitution at … (more)
The p.R190W pathogenic mutation (also known as c.568C>T), located in coding exon 3 of the LMNA gene, results from a C to T substitution at nucleotide position 568. The arginine at codon 190 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration has been reported in a number of individuals with dilated cardiomyopathy including one reported de novo case, and segregation studies have identified a strong disease association (Arbustini E et al. J. Am. Coll. Cardiol., 2002 Mar;39:981-90; Hermida-Prieto M et al. Am. J. Cardiol., 2004 Jul;94:50-4; Sylvius N et al. J. Med. Genet., 2005 Aug;42:639-47; Kärkkäinen S et al. Heart, 2006 Apr;92:524-6; Song K et al. Exp. Mol. Med., 2007 Feb;39:114-20; Vaikhanskaya T et al. Oxf Med Case Reports, 2014 Sep;2014:102-4; Cuenca S et al. J. Heart Lung Transplant., 2016 May;35:625-35). In vitro studies have suggested that this alteration would alter protein structure and self-association behavior (Banerjee A et al. PLoS ONE, 2013 Dec;8:e83410; Bhattacharjee P et al. Biochemistry, 2013 Jun;52:4229-41). 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
(May 01, 2016)
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no assertion criteria provided
Method: clinical testing
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Dilated cardiomyopathy 1S
Affected status: yes
Allele origin:
germline
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Institut für Laboratoriums- und Transfusionsmedizin, Herz- und Diabeteszentrum Nordrhein-Westfalen
Accession: SCV000298111.1
First in ClinVar: Jun 25, 2017 Last updated: Jun 25, 2017 |
Number of individuals with the variant: 1
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics, Academic Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001925111.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Genome Diagnostics Laboratory, University Medical Center Utrecht
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001929734.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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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: SCV001951920.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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Pathogenic
(Sep 16, 2018)
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no assertion criteria provided
Method: research
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not provided
Affected status: yes
Allele origin:
germline
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Gharavi Laboratory, Columbia University
Accession: SCV000809471.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
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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: SCV000088533.1
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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Implications of Genetic Testing in Dilated Cardiomyopathy. | Verdonschot JAJ | Circulation. Genomic and precision medicine | 2020 | PMID: 32880476 |
Genetic Basis and Genotype-Phenotype Correlations in Han Chinese Patients with Idiopathic Dilated Cardiomyopathy. | Zhang XL | Scientific reports | 2020 | PMID: 32041989 |
A novel LMNA nonsense mutation causes two distinct phenotypes of cardiomyopathy with high risk of sudden cardiac death in a large five-generation family. | Glöcklhofer CR | Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology | 2018 | PMID: 29947763 |
Genetic basis of familial dilated cardiomyopathy patients undergoing heart transplantation. | Cuenca S | The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation | 2016 | PMID: 26899768 |
Targeted Next-Generation Sequencing Reveals Hot Spots and Doubly Heterozygous Mutations in Chinese Patients with Familial Cardiomyopathy. | Zhao Y | BioMed research international | 2015 | PMID: 26199943 |
LMNA-related dilated cardiomyopathy. | Vaikhanskaya T | Oxford medical case reports | 2014 | PMID: 25988045 |
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 |
Genetic analysis in 418 index patients with idiopathic dilated cardiomyopathy: overview of 10 years' experience. | van Spaendonck-Zwarts KY | European journal of heart failure | 2013 | PMID: 23349452 |
Mutations in the Lamin A/C gene mimic arrhythmogenic right ventricular cardiomyopathy. | Quarta G | European heart journal | 2012 | PMID: 22199124 |
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 |
Lamin A/C mutations associated with familial and sporadic cases of dilated cardiomyopathy in Koreans. | Song K | Experimental & molecular medicine | 2007 | PMID: 17334235 |
Novel mutations in the lamin A/C gene in heart transplant recipients with end stage dilated cardiomyopathy. | Kärkkäinen S | Heart (British Cardiac Society) | 2006 | PMID: 16537768 |
In vivo and in vitro examination of the functional significances of novel lamin gene mutations in heart failure patients. | Sylvius N | Journal of medical genetics | 2005 | PMID: 16061563 |
LMNA mutations in cardiac transplant recipients. | Pethig K | Cardiology | 2005 | PMID: 15539782 |
Familial dilated cardiomyopathy and isolated left ventricular noncompaction associated with lamin A/C gene mutations. | Hermida-Prieto M | The American journal of cardiology | 2004 | PMID: 15219508 |
Autosomal dominant dilated cardiomyopathy with atrioventricular block: a lamin A/C defect-related disease. | Arbustini E | Journal of the American College of Cardiology | 2002 | PMID: 11897440 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=LMNA | - | - | - | - |
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Text-mined citations for rs59026483 ...
HelpRecord last updated May 19, 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.