ClinVar Genomic variation as it relates to human health
NM_000257.4(MYH7):c.4259G>A (p.Arg1420Gln)
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_000257.4(MYH7):c.4259G>A (p.Arg1420Gln)
Variation ID: 43004 Accession: VCV000043004.31
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 14q11.2 14: 23417597 (GRCh38) [ NCBI UCSC ] 14: 23886806 (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 11, 2015 May 1, 2024 Jan 17, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000257.4:c.4259G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000248.2:p.Arg1420Gln missense NC_000014.9:g.23417597C>T NC_000014.8:g.23886806C>T NG_007884.1:g.23065G>A LRG_384:g.23065G>A LRG_384t1:c.4259G>A - Protein change
- R1420Q
- Other names
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- Canonical SPDI
- NC_000014.9:23417596: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.
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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
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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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MYH7 | No evidence available | No evidence available |
GRCh38 GRCh37 |
3602 | 4859 |
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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Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Oct 3, 2023 | RCV000035898.14 | |
Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Dec 12, 2023 | RCV000200190.14 | |
Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jan 17, 2024 | RCV000770479.7 | |
Pathogenic (1) |
criteria provided, single submitter
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Jun 13, 2023 | RCV003317057.1 | |
Likely pathogenic (1) |
criteria provided, single submitter
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May 7, 2021 | RCV002326727.2 |
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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Likely pathogenic
(Apr 30, 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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Blueprint Genetics
Accession: SCV000927243.1
First in ClinVar: Jul 25, 2019 Last updated: Jul 25, 2019
Comment:
Patient analyzed with Hypertrophic Cardiomyopathy (HCM) Panel
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Likely pathogenic
(Aug 23, 2018)
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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
Accession: SCV000901922.2
First in ClinVar: May 06, 2019 Last updated: May 31, 2020 |
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Likely pathogenic
(Aug 14, 2019)
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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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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000059549.6
First in ClinVar: May 03, 2013 Last updated: Jul 03, 2020 |
Comment:
proposed classification - variant undergoing re-assessment, contact laboratory
Number of individuals with the variant: 4
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Likely pathogenic
(Oct 03, 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: SCV000208582.14
First in ClinVar: Feb 24, 2015 Last updated: Oct 05, 2023 |
Comment:
Identified in patients with HCM or sudden death in published literature (Lopes et al., 2015; Walsh et al., 2017; Bartot et al., 2011; Wang et … (more)
Identified in patients with HCM or sudden death in published literature (Lopes et al., 2015; Walsh et al., 2017; Bartot et al., 2011; Wang et al., 2014; Murphy et al., 2016; Lahrouchi et al., 2017; Sheikh et al., 2018; van Lint et al., 2019; Nakashima et al., 2020; Park et al., 2022); 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: 21817903, 25351510, 27532257, 28449774, 26914223, 29764897, 30847666, 27247418, 34542152, 33487615, 32830170, 15358028, 25132132) (less)
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Likely pathogenic
(Jun 27, 2023)
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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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Revvity Omics, Revvity
Accession: SCV003834063.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
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Likely pathogenic
(Jan 17, 2024)
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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: SCV001351781.3
First in ClinVar: Jun 22, 2020 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces arginine with glutamine at codon 1420 in the LMM domain of the MYH7 protein. Computational prediction tools indicate that this variant … (more)
This missense variant replaces arginine with glutamine at codon 1420 in the LMM domain of the MYH7 protein. Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in more than 10 individuals affected with hypertrophic cardiomyopathy (PMID: 21817903, 25132132, 25351510, 26914223, 27532257, 27247418, 29764897, 32481709, 33487615, 33495597, 34542152) and in one individual affected with sudden arrhythmic death syndrome (PMID: 28449774). A different variant affecting the same codon, p.Arg1420Trp, is considered to be disease-causing (ClinVar variation ID: 43003), suggesting that arginine at this position is important for MYH7 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 Likely Pathogenic. (less)
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Pathogenic
(Dec 12, 2023)
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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: SCV000253684.7
First in ClinVar: Oct 11, 2015 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1420 of the MYH7 protein (p.Arg1420Gln). … (more)
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1420 of the MYH7 protein (p.Arg1420Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with sudden cardiac death and hypertrophic cardiomyopathy (PMID: 21817903, 25351510, 26914223, 27247418, 27532257, 28449774; Invitae). ClinVar contains an entry for this variant (Variation ID: 43004). 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 MYH7 protein function with a positive predictive value of 95%. This variant disrupts the p.Arg1420 amino acid residue in MYH7. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15358028, 20624503, 23283745, 27532257). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
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Likely Pathogenic
(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: SCV004844778.1
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 glutamine at codon 1420 in the LMM domain of the MYH7 protein. Computational prediction suggests that this variant may … (more)
This missense variant replaces arginine with glutamine at codon 1420 in the LMM domain of the MYH7 protein. Computational prediction suggests that this variant may have a 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 more than 10 individuals affected with hypertrophic cardiomyopathy (PMID: 21817903, 25132132, 25351510, 26914223, 27532257, 27247418, 29764897, 32481709, 33487615) and in one individual with sudden arrhythmic death syndrome (PMID: 28449774). A different variant affecting the same codon, p.Arg1420Trp, is considered to be disease-causing (ClinVar variation ID: 43003), suggesting that arginine at this position is important for MYH7 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 Likely Pathogenic. (less)
Number of individuals with the variant: 1
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Pathogenic
(Jun 13, 2023)
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criteria provided, single submitter
Method: clinical testing
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Primary familial hypertrophic cardiomyopathy
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV004020525.1
First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023 |
Comment:
Variant summary: MYH7 c.4259G>A (p.Arg1420Gln) results in a conservative amino acid change located in the myosin tail domain (IPR002928) of the encoded protein sequence. Four … (more)
Variant summary: MYH7 c.4259G>A (p.Arg1420Gln) results in a conservative amino acid change located in the myosin tail domain (IPR002928) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251476 control chromosomes. c.4259G>A has been reported in the literature in many individuals affected with hypertrophic cardiomyopathy and in at least one individual with sudden unexplained death (e.g., Bartot_2011, Lopes_2015, Murphy_2016, Magri_2020, Wang_2014, Nakashima_2020, Larouchi_2017), indicating that this variant is very likely to be associated with disease. Additionally, other variants at the Arg1420 residue have been reported as associated with disease (e.g., p.Arg1420Trp), suggesting that this codon is functionally important. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 30731207, 27247418, 28449774, 32481709, 26914223, 32830170, 34542152, 29764897, 27532257, 30696458, 25132132, 25351510). Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Six laboratories classified the variant as likely pathogenic, one classified it as pathogenic, and one classified it as a variant of uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Likely pathogenic
(May 07, 2021)
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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: SCV002627717.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.R1420Q variant (also known as c.4259G>A), located in coding exon 29 of the MYH7 gene, results from a G to A substitution at nucleotide … (more)
The p.R1420Q variant (also known as c.4259G>A), located in coding exon 29 of the MYH7 gene, results from a G to A substitution at nucleotide position 4259. The arginine at codon 1420 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been reported in numerous individuals with hypertrophic cardiomyopathy (HCM) (Van Driest SL et al. J Am Coll Cardiol, 2004 Aug;44:602-10; Bortot B et al. Diagn Mol Pathol, 2011 Sep;20:175-9; Wang J et al. Eur J Heart Fail, 2014 Sep;16:950-7; Lopes LR et al. Heart, 2015 Feb;101:294-301; Homburger JR et al. Proc Natl Acad Sci U S A, 2016 06;113:6701-6; Walsh R et al. Genet Med, 2017 02;19:192-203; Sheikh N et al. Circulation, 2018 09;138:1184-1194; Nakashima Y et al. Circ J, 2020 09;84:1846-1853). 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 majority of available evidence to date, this variant is likely to be pathogenic. (less)
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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A genome-first approach to rare variants in hypertrophic cardiomyopathy genes MYBPC3 and MYH7 in a medical biobank. | Park J | Human molecular genetics | 2022 | PMID: 34542152 |
Common genetic variants and modifiable risk factors underpin hypertrophic cardiomyopathy susceptibility and expressivity. | Harper AR | Nature genetics | 2021 | PMID: 33495597 |
A Validation Study of the Mayo Clinic Phenotype-Based Genetic Test Prediction Score for Japanese Patients With Hypertrophic Cardiomyopathy. | Moriki T | Circulation journal : official journal of the Japanese Circulation Society | 2021 | PMID: 33487615 |
Lifelong Clinical Impact of the Presence of Sarcomere Gene Mutation in Japanese Patients With Hypertrophic Cardiomyopathy. | Nakashima Y | Circulation journal : official journal of the Japanese Circulation Society | 2020 | PMID: 32830170 |
Risk Stratification in Hypertrophic Cardiomyopathy. Insights from Genetic Analysis and Cardiopulmonary Exercise Testing. | Magrì D | Journal of clinical medicine | 2020 | PMID: 32481709 |
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 |
Genetic Diagnostic Testing for Inherited Cardiomyopathies: Considerations for Offering Multi-Gene Tests in a Health Care Setting. | Daoud H | The Journal of molecular diagnostics : JMD | 2019 | PMID: 30731207 |
Quantitative approaches to variant classification increase the yield and precision of genetic testing in Mendelian diseases: the case of hypertrophic cardiomyopathy. | Walsh R | Genome medicine | 2019 | PMID: 30696458 |
Diagnostic Yield of Genetic Testing in Young Athletes With T-Wave Inversion. | Sheikh N | Circulation | 2018 | PMID: 29764897 |
Utility of Post-Mortem Genetic Testing in Cases of Sudden Arrhythmic Death Syndrome. | Lahrouchi N | Journal of the American College of Cardiology | 2017 | PMID: 28449774 |
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 |
Multidimensional structure-function relationships in human β-cardiac myosin from population-scale genetic variation. | Homburger JR | Proceedings of the National Academy of Sciences of the United States of America | 2016 | PMID: 27247418 |
Evaluation of the Mayo Clinic Phenotype-Based Genotype Predictor Score in Patients with Clinically Diagnosed Hypertrophic Cardiomyopathy. | Murphy SL | Journal of cardiovascular translational research | 2016 | PMID: 26914223 |
Novel genotype-phenotype associations demonstrated by high-throughput sequencing in patients with hypertrophic cardiomyopathy. | Lopes LR | Heart (British Cardiac Society) | 2015 | PMID: 25351510 |
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 |
Multiple gene mutations, not the type of mutation, are the modifier of left ventricle hypertrophy in patients with hypertrophic cardiomyopathy. | Zou Y | Molecular biology reports | 2013 | PMID: 23283745 |
High-throughput genotyping robot-assisted method for mutation detection in patients with hypertrophic cardiomyopathy. | Bortot B | Diagnostic molecular pathology : the American journal of surgical pathology, part B | 2011 | PMID: 21817903 |
Prevalence and spectrum of mutations in a cohort of 192 unrelated patients with hypertrophic cardiomyopathy. | Millat G | European journal of medical genetics | 2010 | PMID: 20624503 |
Comprehensive analysis of the beta-myosin heavy chain gene in 389 unrelated patients with hypertrophic cardiomyopathy. | Van Driest SL | Journal of the American College of Cardiology | 2004 | PMID: 15358028 |
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Text-mined citations for rs397516207 ...
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.