ClinVar Genomic variation as it relates to human health
NM_000257.4(MYH7):c.2782G>A (p.Asp928Asn)
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.2782G>A (p.Asp928Asn)
Variation ID: 164313 Accession: VCV000164313.15
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 14q11.2 14: 23424047 (GRCh38) [ NCBI UCSC ] 14: 23893256 (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 Feb 2, 2015 Feb 20, 2024 Sep 24, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000257.4:c.2782G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000248.2:p.Asp928Asn missense NC_000014.9:g.23424047C>T NC_000014.8:g.23893256C>T NG_007884.1:g.16615G>A LRG_384:g.16615G>A LRG_384t1:c.2782G>A P12883:p.Asp928Asn - Protein change
- D928N
- Other names
- p.D928N:GAT>AAT
- Canonical SPDI
- NC_000014.9:23424046: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) 0.00000
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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MYH7 | No evidence available | No evidence available |
GRCh38 GRCh37 |
3578 | 4827 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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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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Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Mar 21, 2023 | RCV000158574.6 | |
Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Sep 24, 2023 | RCV000527742.9 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Sep 24, 2019 | RCV000622071.2 |
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
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
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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
(Aug 26, 2014)
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criteria provided, single submitter
Method: clinical testing
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Hypertrophic cardiomyopathy
(Autosomal dominant inheritance)
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000199167.4
First in ClinVar: Feb 02, 2015 Last updated: Feb 02, 2015 |
Comment:
The Asp928Asn variant in MYH7 has been reported in 3 individuals with HCM and se gregated with disease in at least 2 affected relatives from … (more)
The Asp928Asn variant in MYH7 has been reported in 3 individuals with HCM and se gregated with disease in at least 2 affected relatives from 2 families (Erdmann 2003, Perrot 2005, Gimeno 2009). In addition, this variant has also been identif ied by our laboratory in 2 individuals with HCM and segregated with disease in 2 affected relatives. It has not been identified in large population studies. Com putational prediction tools and conservation analysis do not provide strong supp ort for or against an impact to the protein. In summary, although additional stu dies are required to fully establish its clinical significance, its absence in c ontrol populations and segregation with disease support that this variant is lik ely pathogenic. (less)
Number of individuals with the variant: 9
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Likely pathogenic
(Sep 24, 2019)
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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: SCV000740215.4
First in ClinVar: Apr 14, 2018 Last updated: Nov 29, 2022 |
Comment:
The p.D928N variant (also known as c.2782G>A), located in coding exon 21 of the MYH7 gene, results from a G to A substitution at nucleotide … (more)
The p.D928N variant (also known as c.2782G>A), located in coding exon 21 of the MYH7 gene, results from a G to A substitution at nucleotide position 2782. The aspartic acid at codon 928 is replaced by asparagine, an amino acid with highly similar properties. This alteration has been reported in multiple unrelated individuals with hypertrophic cardiomyopathy (HCM) and showed some limited segregation with disease (Erdmann J et al. Clin Genet. 2003 Oct;64(4):339-49; Perrot AJ Mol. Med. 2005 Jun;83(6):468-77; Gimeno JR Rev Esp Cardiol. 2009 Dec;62(12):1473-7; García-Molina E et al. Am J Transl Res. 2019 Mar;11(3):1724-1735). Other alterations affecting this amino acid (p.D928A, p.D928G, and p.D928V) have been reported in individuals with HCM (Michels M. Eur. Heart J. 2009 Nov;30(21):2593-8; Lopes LR et al. Heart, 2015 Feb;101:294-301; Walsh R et al. Genet. Med., 2017 Feb;19:192-203). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. (less)
Number of individuals with the variant: 1
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Pathogenic
(Jun 22, 2022)
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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: SCV000208509.14
First in ClinVar: Feb 24, 2015 Last updated: Mar 04, 2023 |
Comment:
Reported in multiple unrelated individuals with HCM in the published literature (Erdmann et al., 2003; Perrot et al., 2005; Gimeno et al., 2009; Walsh et … (more)
Reported in multiple unrelated individuals with HCM in the published literature (Erdmann et al., 2003; Perrot et al., 2005; Gimeno et al., 2009; Walsh et al., 2017; Weissler-Snir et al., 2017; Perez-Sanchez et al., 2017; Viswanathan 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: 20038417, 23982742, 15856146, 12974739, 27532257, 28193612, 28606303, 28687478, 29121657, 30972196, 29300372) (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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not provided
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV004238298.1
First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024 |
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Pathogenic
(Sep 24, 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: SCV000623684.6
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. This variant is found within a region of MYH7 between codons 181 and 937 that … (more)
For these reasons, this variant has been classified as Pathogenic. This variant is found within a region of MYH7 between codons 181 and 937 that contains the majority of the myosin head domain. Missense variants in this region have been shown to be significantly overrepresented in individuals with hypertrophic cardiomyopathy (PMID: 27532257). 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. ClinVar contains an entry for this variant (Variation ID: 164313). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 12974739, 15856146, 20038417, 27532257, 28193612). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 928 of the MYH7 protein (p.Asp928Asn). (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 study of the pathogenicity of variants in familial heart disease. The value of cosegregation. | García-Molina E | American journal of translational research | 2019 | PMID: 30972196 |
Hypertrophic cardiomyopathy clinical phenotype is independent of gene mutation and mutation dosage. | Viswanathan SK | PloS one | 2017 | PMID: 29121657 |
Lack of Phenotypic Differences by Cardiovascular Magnetic Resonance Imaging in MYH7 (β-Myosin Heavy Chain)- Versus MYBPC3 (Myosin-Binding Protein C)-Related Hypertrophic Cardiomyopathy. | Weissler-Snir A | Circulation. Cardiovascular imaging | 2017 | PMID: 28193612 |
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 |
Novel genotype-phenotype associations demonstrated by high-throughput sequencing in patients with hypertrophic cardiomyopathy. | Lopes LR | Heart (British Cardiac Society) | 2015 | PMID: 25351510 |
Hypertrophic cardiomyopathy. A study of the troponin-T gene in 127 Spanish families. | Gimeno JR | Revista espanola de cardiologia | 2009 | PMID: 20038417 |
Disease penetrance and risk stratification for sudden cardiac death in asymptomatic hypertrophic cardiomyopathy mutation carriers. | Michels M | European heart journal | 2009 | PMID: 19666645 |
Prevalence of cardiac beta-myosin heavy chain gene mutations in patients with hypertrophic cardiomyopathy. | Perrot A | Journal of molecular medicine (Berlin, Germany) | 2005 | PMID: 15856146 |
Mutation spectrum in a large cohort of unrelated consecutive patients with hypertrophic cardiomyopathy. | Erdmann J | Clinical genetics | 2003 | PMID: 12974739 |
Text-mined citations for rs727503252 ...
HelpRecord last updated Mar 17, 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.