ClinVar Genomic variation as it relates to human health
NM_170707.4(LMNA):c.565C>T (p.Arg189Trp)
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.565C>T (p.Arg189Trp)
Variation ID: 66906 Accession: VCV000066906.21
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1q22 1: 156134454 (GRCh38) [ NCBI UCSC ] 1: 156104245 (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 1, 2024 Dec 21, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_170707.4:c.565C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_733821.1:p.Arg189Trp missense NM_005572.4:c.565C>T MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_005563.1:p.Arg189Trp missense NM_001257374.3:c.229C>T NP_001244303.1:p.Arg77Trp missense NM_001282624.2:c.322C>T NP_001269553.1:p.Arg108Trp missense NM_001282625.2:c.565C>T NP_001269554.1:p.Arg189Trp missense NM_001282626.2:c.565C>T NP_001269555.1:p.Arg189Trp missense NM_170708.4:c.565C>T NP_733822.1:p.Arg189Trp missense NC_000001.11:g.156134454C>T NC_000001.10:g.156104245C>T NG_008692.2:g.56882C>T LRG_254:g.56882C>T LRG_254t2:c.565C>T - Protein change
- R189W, R77W, R108W
- Other names
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- Canonical SPDI
- NC_000001.11:156134453: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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0.00040 (T)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00001
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00002
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
1000 Genomes Project 30x 0.00031
1000 Genomes Project 0.00040
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 | ||
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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
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. |
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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
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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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Uncertain significance (2) |
criteria provided, single submitter
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Jun 5, 2023 | RCV000057417.2 | |
Uncertain significance (2) |
criteria provided, single submitter
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Oct 2, 2023 | RCV000148603.4 | |
Uncertain significance (1) |
criteria provided, single submitter
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Dec 21, 2023 | RCV000794744.8 | |
Uncertain significance (1) |
criteria provided, single submitter
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Sep 14, 2023 | RCV001177403.4 | |
Likely pathogenic (1) |
no assertion criteria provided
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Apr 27, 2021 | RCV001775077.1 | |
Uncertain significance (1) |
criteria provided, single submitter
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Mar 23, 2023 | RCV002345365.3 | |
Uncertain significance (1) |
criteria provided, single submitter
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Oct 21, 2021 | RCV002477186.1 |
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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Uncertain significance
(Dec 21, 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: SCV000934170.6
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 189 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 189 of the LMNA protein (p.Arg189Trp). This variant is present in population databases (rs267607626, gnomAD 0.005%). This missense change has been observed in individual(s) with dilated cardiomyopathy and/or limb-girdle muscular dystrophy (PMID: 20307303, 22326558, 33963534, 34768595). This variant is also known as c.229C>T; p.Arg77Trp. ClinVar contains an entry for this variant (Variation ID: 66906). 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%. This variant disrupts the p.Arg189 amino acid residue in LMNA. Other variant(s) that disrupt this residue have been observed in individuals with LMNA-related conditions (PMID: 20848652), which suggests that this may be a clinically significant amino acid residue. 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
(Sep 14, 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: SCV001341605.3
First in ClinVar: Jun 22, 2020 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces arginine with tryptophan at codon 189 of the LMNA protein. Computational prediction is inconclusive regarding the impact of this variant on … (more)
This missense variant replaces arginine with tryptophan at codon 189 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, cardiac conduction abnormalities and a strong family history of sudden cardiac death (PMID: 20307303). This variant has also been reported in an individual with dilated cardiomyopathy, limb-girdle muscular dystrophy and peripheral neuropathy (PMID: 22326558), and in an individual with dilated cardiomyopathy (PMID: 34768595). This variant has been identified in 5/282762 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
(Oct 21, 2021)
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criteria provided, single submitter
Method: clinical testing
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Dilated cardiomyopathy 1A
Familial partial lipodystrophy, Dunnigan type Hutchinson-Gilford syndrome Emery-Dreifuss muscular dystrophy 2, autosomal dominant Emery-Dreifuss muscular dystrophy 2, autosomal dominant Dilated cardiomyopathy-hypergonadotropic hypogonadism syndrome Mandibuloacral dysplasia with type A lipodystrophy Charcot-Marie-Tooth disease type 2B1 Heart-hand syndrome, Slovenian type Congenital muscular dystrophy due to LMNA mutation Emery-Dreifuss muscular dystrophy 3, autosomal recessive Restrictive dermopathy 2
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002786998.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Uncertain significance
(Jun 05, 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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GeneDx
Accession: SCV003936492.1
First in ClinVar: Jul 08, 2023 Last updated: Jul 08, 2023 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant … (more)
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24846508, 23299917, 25637381, 20307303, 22326558, 20461955, 34862408, 33963534, 23328570, 20848652, 34768595, 10939567) (less)
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Uncertain Significance
(Oct 02, 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: SCV004834644.1
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 189 of the LMNA protein. Computational prediction is inconclusive regarding the impact of this variant on … (more)
This missense variant replaces arginine with tryptophan at codon 189 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with dilated cardiomyopathy, cardiac conduction abnormalities and a strong family history of sudden cardiac death (PMID: 20307303). This variant has been reported in an individual with dilated cardiomyopathy, limb-girdle muscular dystrophy and peripheral neuropathy (PMID: 22326558). This variant has been identified in 5/282762 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: 1
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Uncertain significance
(Mar 23, 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: SCV002653792.3
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.R189W variant (also known as c.565C>T), located in coding exon 3 of the LMNA gene, results from a C to T substitution at nucleotide … (more)
The p.R189W variant (also known as c.565C>T), located in coding exon 3 of the LMNA gene, results from a C to T substitution at nucleotide position 565. The arginine at codon 189 is replaced by tryptophan, an amino acid with dissimilar properties. This variant was detected in an individual with limb-girdle muscular dystrophy, peripheral neuropathy, and dilated cardiomyopathy (DCM), as well as in a female with DCM and family history of sudden cardiac death including two affected obligate carriers (Botto N et al. Cardiovasc Ultrasound, 2010 Mar;8:9; Magagnotti C et al. Biochim. Biophys. Acta, 2012 Jun;1822:970-9). This variant has also been reported in DCM and exome cohorts, but limited or no clinical information was provided (Fontana M et al. JACC Cardiovasc Imaging, 2013 Jan;6:124-6; Andreasen C et al. Eur. J. Hum. Genet., 2013 Sep;21:918-28; Ferradini V et al. J Clin Med, 2021 Oct;10). 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
(Jun 01, 2014)
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no assertion criteria provided
Method: research
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Cardiomyopathy, dilated
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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CSER _CC_NCGL, University of Washington
Study: ESP 6500 variant annotation
Accession: SCV000190318.1 First in ClinVar: Dec 06, 2014 Last updated: Dec 06, 2014
Comment:
Variants classified for the Actionable exomic incidental findings in 6503 participants: challenges of variant classification manuscript
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Likely pathogenic
(Apr 27, 2021)
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no assertion criteria provided
Method: clinical testing
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CARDIOMYOPATHY, DILATED, 1A
Affected status: yes
Allele origin:
germline
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Sangiuolo Lab - Medical Genetics Laboratory, Tor Vergata University
Accession: SCV001593104.1
First in ClinVar: Nov 11, 2021 Last updated: Nov 11, 2021 |
Number of individuals with the variant: 1
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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: SCV000088531.1
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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Clinical Features of LMNA-Related Cardiomyopathy in 18 Patients and Characterization of Two Novel Variants. | Ferradini V | Journal of clinical medicine | 2021 | PMID: 34768595 |
Mutation spectrum of hereditary myopathies in Turkish patients and novel variants. | Saat H | Annals of human genetics | 2021 | PMID: 33963534 |
CMR-verified interstitial myocardial fibrosis as a marker of subclinical cardiac involvement in LMNA mutation carriers. | Fontana M | JACC. Cardiovascular imaging | 2013 | PMID: 23328570 |
New population-based exome data are questioning the pathogenicity of previously cardiomyopathy-associated genetic variants. | Andreasen C | European journal of human genetics : EJHG | 2013 | PMID: 23299917 |
Protein profiling reveals energy metabolism and cytoskeletal protein alterations in LMNA mutation carriers. | Magagnotti C | Biochimica et biophysica acta | 2012 | PMID: 22326558 |
Novel LMNA mutations in patients with Emery-Dreifuss muscular dystrophy and functional characterization of four LMNA mutations. | Scharner J | Human mutation | 2011 | PMID: 20848652 |
Text-mined citations for rs267607626 ...
HelpRecord last updated May 08, 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.