ClinVar Genomic variation as it relates to human health
NM_000258.3(MYL3):c.466G>A (p.Val156Met)
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.
Likely pathogenic(3); Uncertain significance(7)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000258.3(MYL3):c.466G>A (p.Val156Met)
Variation ID: 31778 Accession: VCV000031778.33
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p21.31 3: 46859490 (GRCh38) [ NCBI UCSC ] 3: 46900980 (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 4, 2013 Apr 20, 2024 Jan 31, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000258.3:c.466G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000249.1:p.Val156Met missense NC_000003.12:g.46859490C>T NC_000003.11:g.46900980C>T NG_007555.2:g.27680G>A LRG_395:g.27680G>A LRG_395t1:c.466G>A LRG_395p1:p.Val156Met - Protein change
- V156M
- Other names
- p.V156M:GTG>ATG
- Canonical SPDI
- NC_000003.12:46859489:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- functional variant Sequence Ontology [SO:0001536]
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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.
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
Trans-Omics for Precision Medicine (TOPMed) 0.00005
The Genome Aggregation Database (gnomAD) 0.00004
Exome Aggregation Consortium (ExAC) 0.00002
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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MYL3 | No evidence available | No evidence available |
GRCh38 GRCh37 |
412 | 423 |
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 (4) |
criteria provided, multiple submitters, no conflicts
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Aug 28, 2023 | RCV000024469.12 | |
Uncertain significance (1) |
no assertion criteria provided
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Jun 1, 2014 | RCV000148717.2 | |
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Jan 31, 2024 | RCV000196294.9 | |
Uncertain significance (1) |
criteria provided, single submitter
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Mar 11, 2023 | RCV000617202.3 | |
Uncertain significance (1) |
criteria provided, single submitter
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Dec 22, 2016 | RCV000624899.3 | |
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Mar 21, 2023 | RCV000769165.8 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jan 3, 2022 | RCV001807740.1 |
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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Likely pathogenic
(Jan 03, 2022)
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criteria provided, single submitter
Method: clinical testing
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Hypertrophic cardiomyopathy 8
Affected status: yes
Allele origin:
germline
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3billion
Accession: SCV002058425.1
First in ClinVar: Jan 15, 2022 Last updated: Jan 15, 2022 |
Comment:
Same nucleotide change resulting in same amino acid change has been previously reported to be associated with MYL3 related disorder (PMID:16754800, PS1_P). A different missense … (more)
Same nucleotide change resulting in same amino acid change has been previously reported to be associated with MYL3 related disorder (PMID:16754800, PS1_P). A different missense change at the same codon has been reported to be associated with MYL3 related disorder (PMID:25132132, PM5_P). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.926, 3CNET: 0.975, PP3_P). A missense variant is a common mechanism associated with Cardiomyopathy (PP2_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000021, PM2_M). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Left ventricular hypertrophy (present)
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Uncertain significance
(Aug 28, 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: SCV000208887.14
First in ClinVar: Feb 24, 2015 Last updated: Sep 07, 2023 |
Comment:
Identified in several unrelated patients with HCM or other cardiac findings (Morita et al., 2006; Ho et al., 2013; Jay et al., 2013; Berge et … (more)
Identified in several unrelated patients with HCM or other cardiac findings (Morita et al., 2006; Ho et al., 2013; Jay et al., 2013; Berge et al., 2014; Amendola et al., 2015; Walsh et al., 2017); 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: 25637381, 24111713, 16754800, 23594557, 27532257, 23549607, 35653365, 30665703) (less)
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Likely pathogenic
(Mar 21, 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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CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Study: Canadian Open Genetics Repository
Accession: SCV000900540.3 First in ClinVar: May 06, 2019 Last updated: Feb 04, 2024 |
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Likely pathogenic
(Jan 31, 2024)
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criteria provided, single submitter
Method: clinical testing
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Hypertrophic cardiomyopathy
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000254449.8
First in ClinVar: Oct 11, 2015 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 156 of the MYL3 protein (p.Val156Met). … (more)
This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 156 of the MYL3 protein (p.Val156Met). This variant is present in population databases (rs199474707, gnomAD 0.004%). This missense change has been observed in individuals with clinical features of hypertrophic cardiomyopathy (PMID: 16754800, 23549607, 24111713, 27532257; Invitae). ClinVar contains an entry for this variant (Variation ID: 31778). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. This variant disrupts the p.Met156 amino acid residue in MYL3. Other variant(s) that disrupt this residue have been observed in individuals with MYL3-related conditions (PMID: 25132132), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. (less)
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Uncertain significance
(Dec 22, 2016)
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criteria provided, single submitter
Method: clinical testing
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Primary familial hypertrophic cardiomyopathy
Affected status: yes
Allele origin:
germline
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Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute
Accession: SCV000740626.1
First in ClinVar: Apr 15, 2018 Last updated: Apr 15, 2018 |
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Uncertain significance
(Aug 10, 2018)
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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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Blueprint Genetics
Accession: SCV000927847.1
First in ClinVar: Jul 25, 2019 Last updated: Jul 25, 2019 |
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Uncertain significance
(Mar 11, 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: SCV000739969.5
First in ClinVar: Apr 14, 2018 Last updated: Apr 15, 2023 |
Comment:
The p.V156M variant (also known as c.466G>A), located in coding exon 4 of the MYL3 gene, results from a G to A substitution at nucleotide … (more)
The p.V156M variant (also known as c.466G>A), located in coding exon 4 of the MYL3 gene, results from a G to A substitution at nucleotide position 466. The valine at codon 156 is replaced by methionine, an amino acid with highly similar properties. This alteration has been detected in individuals from a hypertrophic cardiomyopathy (HCM) cohorts, HCM genetic testing cohorts, and an individual reported to have left ventricular hypertrophy, though clinical details were limited (Ho CY et al. Circ Cardiovasc Imaging. 2013;6:415-22; Berge KE et al. Clin Genet. 2014;86:355-60; Walsh R et al. Genet Med. 2017 02;19(2):192-203). This alteration was also reported in two individuals from the Framingham Heart Study, neither of whom had increased left ventricular wall thickness, though one had atrial enlargement and enhanced fractional shortening (Morita H et al. Circulation. 2006;113:2697-705). This variant has also been seen in cohorts not selected for the presence of HCM, but cardiovascular history was not provided (Amendola LM et al. Genome Res. 2015;25:305-15; Wright CF et al. Am J Hum Genet. 2019 Feb;104(2):275-286). 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
(Nov 17, 2022)
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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: SCV001344277.3
First in ClinVar: Jun 22, 2020 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces valine with methionine at codon 156 of the MYL3 protein. Computational prediction suggests that this variant may have deleterious impact on … (more)
This missense variant replaces valine with methionine at codon 156 of the MYL3 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in several individuals affected with hypertrophic cardiomyopathy (PMID: 23549607, 24111713, 27532257, 33495597) and in an individual showing early signs of left ventricular wall thickening (PMID 16754800). This variant has been identified in 6/282752 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
(Aug 15, 2023)
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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: SCV004843320.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
This missense variant replaces valine with methionine at codon 156 of the MYL3 protein. Computational prediction suggests that this variant may have deleterious impact on … (more)
This missense variant replaces valine with methionine at codon 156 of the MYL3 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in several individuals affected with hypertrophic cardiomyopathy (PMID: 23549607, 24111713, 27532257, 33495597) and in an individual showing early signs of left ventricular wall thickening (PMID 16754800). This variant has been identified in 6/282752 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: 10
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Uncertain Significance
(Apr 04, 2019)
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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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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000059678.7
First in ClinVar: May 03, 2013 Last updated: Apr 20, 2024 |
Comment:
Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This variant has been reported in one individual with HCM (Berge 2014) … (more)
Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This variant has been reported in one individual with HCM (Berge 2014) and two FHS offspring, neither of whom had LVWT >13 mm, but one had left atrial enlargement and enhanced fractional shortening (Morita 2006). Clinvar: VUS (GeneDx, Invitae, CSER, Ambry, Montreal Heart Institute). Gnomad: 0.004% (1 AFR allele, 5 NFE alleles). (less)
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Uncertain significance
(Jun 01, 2014)
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no assertion criteria provided
Method: research
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Increased left ventricular wall thickness
(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: SCV000190449.1 First in ClinVar: Dec 06, 2014 Last updated: Dec 06, 2014 |
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not provided
(Mar 18, 2012)
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no classification provided
Method: curation
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not specified
Affected status: not provided
Allele origin:
germline
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Leiden Muscular Dystrophy (MYL3)
Accession: SCV000045772.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
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Germline Functional Evidence
Functional
Help
The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence |
Method
Help
A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter. |
Result
Help
A brief description of the result of this method for 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 functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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has functional consequence
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Leiden Muscular Dystrophy (MYL3)
Accession: SCV000045772.1
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Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Molecular genetics in 4408 cardiomyopathy probands and 3008 relatives in Norway: 17 years of genetic testing in a national laboratory. | Stava TT | European journal of preventive cardiology | 2022 | PMID: 35653365 |
Common genetic variants and modifiable risk factors underpin hypertrophic cardiomyopathy susceptibility and expressivity. | Harper AR | Nature genetics | 2021 | PMID: 33495597 |
Assessing the Pathogenicity, Penetrance, and Expressivity of Putative Disease-Causing Variants in a Population Setting. | Wright CF | American journal of human genetics | 2019 | PMID: 30665703 |
Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples. | Walsh R | Genetics in medicine : official journal of the American College of Medical Genetics | 2017 | PMID: 27532257 |
Actionable exomic incidental findings in 6503 participants: challenges of variant classification. | Amendola LM | Genome research | 2015 | PMID: 25637381 |
Malignant effects of multiple rare variants in sarcomere genes on the prognosis of patients with hypertrophic cardiomyopathy. | Wang J | European journal of heart failure | 2014 | PMID: 25132132 |
Genetics of hypertrophic cardiomyopathy in Norway. | Berge KE | Clinical genetics | 2014 | PMID: 24111713 |
T1 measurements identify extracellular volume expansion in hypertrophic cardiomyopathy sarcomere mutation carriers with and without left ventricular hypertrophy. | Ho CY | Circulation. Cardiovascular imaging | 2013 | PMID: 23549607 |
Burden of rare sarcomere gene variants in the Framingham and Jackson Heart Study cohorts. | Bick AG | American journal of human genetics | 2012 | PMID: 22958901 |
Single-gene mutations and increased left ventricular wall thickness in the community: the Framingham Heart Study. | Morita H | Circulation | 2006 | PMID: 16754800 |
Text-mined citations for rs199474707 ...
HelpRecord last updated Apr 20, 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.