ClinVar Genomic variation as it relates to human health
NM_000257.4(MYH7):c.1405G>A (p.Asp469Asn)
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.1405G>A (p.Asp469Asn)
Variation ID: 177921 Accession: VCV000177921.23
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 14q11.2 14: 23428957 (GRCh38) [ NCBI UCSC ] 14: 23898166 (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 May 29, 2016 May 1, 2024 Dec 22, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000257.4:c.1405G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000248.2:p.Asp469Asn missense NC_000014.9:g.23428957C>T NC_000014.8:g.23898166C>T NG_007884.1:g.11705G>A LRG_384:g.11705G>A LRG_384t1:c.1405G>A - Protein change
- D469N
- Other names
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- Canonical SPDI
- NC_000014.9:23428956: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.
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
The Genome Aggregation Database (gnomAD) 0.00004
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 |
3627 | 4899 |
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 (2) |
criteria provided, single submitter
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Aug 18, 2020 | RCV000154581.8 | |
Uncertain significance (3) |
criteria provided, single submitter
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May 19, 2022 | RCV000766422.5 | |
Uncertain significance (1) |
criteria provided, single submitter
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Dec 22, 2023 | RCV001054042.8 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Dec 1, 2023 | RCV001798499.4 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jan 11, 2023 | RCV002390345.3 |
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 08, 2021)
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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: SCV002042251.1
First in ClinVar: Dec 29, 2021 Last updated: Dec 29, 2021 |
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Uncertain significance
(Dec 22, 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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001218335.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 469 of the MYH7 protein … (more)
This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 469 of the MYH7 protein (p.Asp469Asn). This variant is present in population databases (rs397516106, gnomAD 0.004%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 27247418, 27532257). ClinVar contains an entry for this variant (Variation ID: 177921). 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. 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
(Aug 18, 2020)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000204254.5
First in ClinVar: Jan 31, 2015 Last updated: May 29, 2021 |
Comment:
Variant classified as Uncertain Significance - Favor Pathogenic. The p.Asp469Asn variant in MYH7 has been previously reported in at least 4 individuals with HCM, as … (more)
Variant classified as Uncertain Significance - Favor Pathogenic. The p.Asp469Asn variant in MYH7 has been previously reported in at least 4 individuals with HCM, as well as 4 individuals referred for HCM testing with limited clinical information, 2 of whom harbored pathogenic variants in other cardiomyopathy genes (Homburger 2016 PMID 27247418, Walsh 2017 PMID 27532257, LMM data, ClinVar Variation ID 177921, Invitae and GeneDx pers. comm.). It has also been identified in 0.002% (3/129156) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Furthermore, this variant lies in the head region of the protein and missense variants in this region are statistically more likely to be disease-associated (Walsh 2016 PMID 27532257). In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PS4_Supporting, PM1, PP3. (less)
Number of individuals with the variant: 2
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Uncertain significance
(May 19, 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: SCV000208738.14
First in ClinVar: Feb 24, 2015 Last updated: Mar 04, 2023 |
Comment:
Reported in association with HCM in the published literature (Homburger et al., 2016; Walsh et al., 2017); Identified in individuals referred for HCM genetic testing … (more)
Reported in association with HCM in the published literature (Homburger et al., 2016; Walsh et al., 2017); Identified in individuals referred for HCM genetic testing at GeneDx; however, most probands harbored additional cardiogenetic variants, and segregation data is limited at this time; Not observed at a 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: 27247418, 27532257, 29300372) (less)
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Uncertain Significance
(Dec 01, 2023)
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criteria provided, single submitter
Method: clinical testing
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Cardiomyopathy
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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All of Us Research Program, National Institutes of Health
Accession: SCV004822808.1
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 aspartic acid with asparagine at codon 469 of the MYH7 protein. Computational prediction tools indicate that this variant's impact on protein … (more)
This missense variant replaces aspartic acid with asparagine at codon 469 of the MYH7 protein. Computational prediction tools indicate that this variant's impact on protein structure and function is inconclusive. This variant is found within a highly conserved region of the myosin head domain. Missense variants in this region have been shown to be significantly overrepresented in individuals with affected with hypertrophic cardiomyopathy (PMID: 27532257). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least three individuals affected with hypertrophic cardiomyopathy (PMID: 27247418, 27532257, 33495596, 33495597), and in one individual affected with an unspecified cardiomyopathy (PMID: 33764162). This variant has been identified in 4/282848 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: 2
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Uncertain significance
(Jan 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: SCV002698894.3
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.D469N variant (also known as c.1405G>A), located in coding exon 12 of the MYH7 gene, results from a G to A substitution at nucleotide … (more)
The p.D469N variant (also known as c.1405G>A), located in coding exon 12 of the MYH7 gene, results from a G to A substitution at nucleotide position 1405. The aspartic acid at codon 469 is replaced by asparagine, an amino acid with highly similar properties. This alteration is located in the myosin head domain, which contains a statistically significant clustering of pathogenic missense variants (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; Ambry internal data). This variant has been detected in hypertrophic and/or dilated cardiomyopathy cohorts; however, details were limited and some reported cases may overlap (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; Puckelwartz MJ et al. J Am Heart Assoc, 2021 Apr;10:e019944). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated 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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Likely pathogenic
(-)
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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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Genome Diagnostics Laboratory, University Medical Center Utrecht
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001927021.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021 |
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Likely pathogenic
(-)
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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 DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001969896.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021 |
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Uncertain significance
(Mar 05, 2012)
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no assertion criteria provided
Method: clinical testing
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not specified
Affected status: not provided
Allele origin:
germline
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Stanford Center for Inherited Cardiovascular Disease, Stanford University
Accession: SCV000280301.1
First in ClinVar: May 29, 2016 Last updated: May 29, 2016 |
Comment:
Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case … (more)
Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Asp469Asn (c.1405 G>A) in MYH7 The variant is novel. In silico analysis with PolyPhen-2 predicts the variant to be probably damaging (HumVar score 0.999). The aspartic acid at codon 469 is completely conserved across species, and neighboring amino acids are highly conserved. I could find one nearby variant reported in association with disease, p.Ile462Phe. The variant was reported online in 1 of 61439 individuals in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/ as of November 29th, 2014). The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. Note that other variants with strong evidence for pathogenicity have been seen at similar frequencies in datasets like this so this does not necessarily rule out pathogenicity (Pan et al 2012). (less)
Number of individuals with the variant: 1
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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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Genomic Context Differs Between Human Dilated Cardiomyopathy and Hypertrophic Cardiomyopathy. | Puckelwartz MJ | Journal of the American Heart Association | 2021 | PMID: 33764162 |
Common genetic variants and modifiable risk factors underpin hypertrophic cardiomyopathy susceptibility and expressivity. | Harper AR | Nature genetics | 2021 | PMID: 33495597 |
Shared genetic pathways contribute to risk of hypertrophic and dilated cardiomyopathies with opposite directions of effect. | Tadros R | Nature genetics | 2021 | PMID: 33495596 |
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 |
Text-mined citations for rs397516106 ...
HelpRecord last updated Sep 29, 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.