ClinVar Genomic variation as it relates to human health
NM_005159.5(ACTC1):c.623G>A (p.Arg208His)
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_005159.5(ACTC1):c.623G>A (p.Arg208His)
Variation ID: 520473 Accession: VCV000520473.23
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 15q14 15: 34792275 (GRCh38) [ NCBI UCSC ] 15: 35084476 (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 Apr 15, 2018 May 1, 2024 Jan 8, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_005159.5:c.623G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_005150.1:p.Arg208His missense NC_000015.10:g.34792275C>T NC_000015.9:g.35084476C>T NG_007553.1:g.8452G>A LRG_388:g.8452G>A LRG_388t1:c.623G>A - Protein change
- R208H
- Other names
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- Canonical SPDI
- NC_000015.10:34792274: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.
Trans-Omics for Precision Medicine (TOPMed) 0.00001
Exome Aggregation Consortium (ExAC) 0.00004
The Genome Aggregation Database (gnomAD), exomes 0.00004
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00023
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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ACTC1 | Little evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
3 | 789 | |
GJD2-DT | - | - | - | GRCh38 | - | 769 |
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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Uncertain significance (1) |
criteria provided, single submitter
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Mar 31, 2017 | RCV000623757.3 | |
Uncertain significance (1) |
criteria provided, single submitter
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Oct 29, 2022 | RCV000802461.6 | |
Uncertain significance (1) |
criteria provided, single submitter
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Oct 26, 2023 | RCV001182797.4 | |
Uncertain significance (3) |
criteria provided, single submitter
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May 6, 2020 | RCV001565492.6 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jul 27, 2022 | RCV002360482.2 | |
not provided (1) |
no classification provided
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- | RCV003483691.1 | |
Uncertain significance (1) |
criteria provided, single submitter
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Sep 26, 2022 | RCV003411468.4 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jan 8, 2024 | RCV004002747.2 |
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 31, 2017)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: yes
Allele origin:
germline
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Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute
Accession: SCV000740462.1
First in ClinVar: Apr 15, 2018 Last updated: Apr 15, 2018 |
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Uncertain significance
(Oct 26, 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: SCV001348386.3
First in ClinVar: Jun 22, 2020 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces arginine with histidine at codon 208 of the ACTC1 protein. Computational prediction is inconclusive regarding the impact of this variant on … (more)
This missense variant replaces arginine with histidine at codon 208 of the ACTC1 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 four individuals affected with dilated cardiomyopathy (PMID: 28416588, 30847666, 32880476 and 34935411) and two individuals affected with left ventricular non-compaction (PMID: 28798025, 30471092). This variant has been identified in 10/251470 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 29, 2022)
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criteria provided, single submitter
Method: clinical testing
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Dilated cardiomyopathy 1R
Hypertrophic cardiomyopathy 11 Atrial septal defect 5
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:
germline
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Invitae
Accession: SCV000942293.6
First in ClinVar: Aug 14, 2019 Last updated: Feb 28, 2024 |
Comment:
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 … (more)
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. 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 not expected to disrupt ACTC1 protein function. ClinVar contains an entry for this variant (Variation ID: 520473). This missense change has been observed in individual(s) with dilated cardiomyopathy or left ventricular noncompaction cardiomyopathy (PMID: 28416588, 28798025, 30471092, 32880476, 34088380). This variant is present in population databases (rs142839840, gnomAD 0.01%). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 208 of the ACTC1 protein (p.Arg208His). (less)
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Uncertain significance
(May 06, 2020)
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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: SCV001788847.1
First in ClinVar: Aug 19, 2021 Last updated: Aug 19, 2021 |
Comment:
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in ClinVar as a variant of uncertain significance (ClinVar … (more)
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 520473; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 28416588, 32880476, 30471092, 28798025) (less)
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Uncertain significance
(Sep 26, 2022)
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criteria provided, single submitter
Method: clinical testing
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ACTC1-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004113856.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The ACTC1 c.623G>A variant is predicted to result in the amino acid substitution p.Arg208His. This variant was reported in individuals with dilated cardiomyopathy or left … (more)
The ACTC1 c.623G>A variant is predicted to result in the amino acid substitution p.Arg208His. This variant was reported in individuals with dilated cardiomyopathy or left ventricular noncompaction; however, the pathogenicity was not established (Table S1, Dal Ferro et al. 2017. PubMed ID: 28416588; Table S3, Miszalski-Jamka et al. 2017. PubMed ID: 28798025; Richard et al. 2018. PubMed ID: 30471092; Table S4, Verdonschot et al. 2020. PubMed ID: 32880476; Table S2, Cambon-Viala et al. 2021. PubMed ID: 34088380). This variant is reported in 0.012% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/15-35084476-C-T) and is interpreted as uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/520473/?). A different nucleotide substitution affecting the same amino acid (p.Arg208Cys) has been reported in an individual with left ventricular noncompaction (Table S2, Mazzarotto et al. 2021. PubMed ID: 33500567). At this time, the clinical significance of the c.623G>A (p.Arg208His) variant is uncertain due to the absence of conclusive functional and genetic evidence. (less)
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Uncertain Significance
(Jan 08, 2024)
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criteria provided, single submitter
Method: clinical testing
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Hypertrophic cardiomyopathy
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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All of Us Research Program, National Institutes of Health
Accession: SCV004844824.1
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 histidine at codon 208 of the ACTC1 protein. Computational prediction is inconclusive regarding the impact of this variant on … (more)
This missense variant replaces arginine with histidine at codon 208 of the ACTC1 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 four individuals affected with dilated cardiomyopathy (PMID: 28416588, 30847666, 32880476 and 34935411) and two individuals affected with left ventricular non-compaction (PMID: 28798025, 30471092). This variant has been identified in 10/251470 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
(Jul 27, 2022)
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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: SCV002658255.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.R208H variant (also known as c.623G>A), located in coding exon 4 of the ACTC1 gene, results from a G to A substitution at nucleotide … (more)
The p.R208H variant (also known as c.623G>A), located in coding exon 4 of the ACTC1 gene, results from a G to A substitution at nucleotide position 623. The arginine at codon 208 is replaced by histidine, an amino acid with highly similar properties. This alteration has been reported in cardiomyopathy cohorts, including dilated cardiomyopathy (DCM), left ventricular non-compaction (LVNC), and pediatric cardiomyopathy cohorts; however, clinical details were limited, and additional cardiac variants were detected in some cases (Dal Ferro M et al. Heart, 2017 11;103:1704-1710; Miszalski-Jamka K et al. Circ Cardiovasc Genet, 2017 Aug;10:[ePub ahead of print]; Richard P et al. Clin Genet, 2019 03;95:356-367; van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309; Verdonschot JAJ et al. Circ Genom Precis Med, 2020 10;13:476-487; Cambon-Viala M et al. J Card Fail, 2021 06;27:677-681; Khan RS et al. J Am Heart Assoc, 2022 01;11:e022854). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
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Uncertain significance
(-)
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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: SCV001921161.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021 |
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Uncertain significance
(-)
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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: SCV001957572.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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not provided
(-)
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no classification provided
Method: phenotyping only
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Atrial septal defect 5
Hypertrophic cardiomyopathy 11 Dilated cardiomyopathy 1R Left ventricular noncompaction 1
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 - Invitae Patient Insights Network
Accession: SCV004228794.1
First in ClinVar: Jan 26, 2024 Last updated: Jan 26, 2024 |
Comment:
Variant interpreted as Uncertain significance and reported on 12-28-2020 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the … (more)
Variant interpreted as Uncertain significance and reported on 12-28-2020 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. (less)
Clinical Features:
Thickened skin (present) , Vascular dilatation (present) , Asthma (present) , Obesity (present) , Type 2 diabetes mellitus (present)
Indication for testing: Diagnostic
Age: 30-39 years
Sex: female
Method: Gene Panel Sequencing
Testing laboratory: Invitae
Date variant was reported to submitter: 2020-12-28
Testing laboratory interpretation: Uncertain significance
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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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Genotype and Cardiac Outcomes in Pediatric Dilated Cardiomyopathy. | Khan RS | Journal of the American Heart Association | 2022 | PMID: 34935411 |
Phenotype/Genotype Relationship in Left Ventricular Noncompaction: Ion Channel Gene Mutations Are Associated With Preserved Left Ventricular Systolic Function and Biventricular Noncompaction: Phenotype/Genotype of Noncompaction. | Cambon-Viala M | Journal of cardiac failure | 2021 | PMID: 34088380 |
Implications of Genetic Testing in Dilated Cardiomyopathy. | Verdonschot JAJ | Circulation. Genomic and precision medicine | 2020 | PMID: 32880476 |
Large next-generation sequencing gene panels in genetic heart disease: yield of pathogenic variants and variants of unknown significance. | van Lint FHM | Netherlands heart journal : monthly journal of the Netherlands Society of Cardiology and the Netherlands Heart Foundation | 2019 | PMID: 30847666 |
Targeted panel sequencing in adult patients with left ventricular non-compaction reveals a large genetic heterogeneity. | Richard P | Clinical genetics | 2019 | PMID: 30471092 |
Novel Genetic Triggers and Genotype-Phenotype Correlations in Patients With Left Ventricular Noncompaction. | Miszalski-Jamka K | Circulation. Cardiovascular genetics | 2017 | PMID: 28798025 |
Association between mutation status and left ventricular reverse remodelling in dilated cardiomyopathy. | Dal Ferro M | Heart (British Cardiac Society) | 2017 | PMID: 28416588 |
Text-mined citations for rs142839840 ...
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.