ClinVar Genomic variation as it relates to human health
NM_000257.4(MYH7):c.3116A>G (p.Glu1039Gly)
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.3116A>G (p.Glu1039Gly)
Variation ID: 426200 Accession: VCV000426200.15
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 14q11.2 14: 23422309 (GRCh38) [ NCBI UCSC ] 14: 23891518 (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 22, 2017 Apr 20, 2024 Dec 5, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000257.4:c.3116A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000248.2:p.Glu1039Gly missense NC_000014.9:g.23422309T>C NC_000014.8:g.23891518T>C NG_007884.1:g.18353A>G LRG_384:g.18353A>G LRG_384t1:c.3116A>G - Protein change
- E1039G
- Other names
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- Canonical SPDI
- NC_000014.9:23422308:T:C
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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.
The Genome Aggregation Database (gnomAD) 0.00006
The Genome Aggregation Database (gnomAD), exomes 0.00010
Exome Aggregation Consortium (ExAC) 0.00012
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
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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 (1) |
criteria provided, single submitter
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Nov 5, 2020 | RCV000490053.2 | |
Uncertain significance (1) |
criteria provided, single submitter
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Dec 5, 2023 | RCV000540550.7 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Nov 2, 2023 | RCV001184832.5 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jun 5, 2023 | RCV003302724.1 |
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
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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
(Nov 05, 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: SCV000576585.4
First in ClinVar: May 22, 2017 Last updated: May 22, 2017 |
Comment:
Reported in a Polish female with HCM who also harbored a pathogenic nonsense MYBPC3 variant; the MYH7 variant did not segregate with disease in the … (more)
Reported in a Polish female with HCM who also harbored a pathogenic nonsense MYBPC3 variant; the MYH7 variant did not segregate with disease in the proband's affected sister (Lipari et al., 2020); 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# 426200; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 31919335) (less)
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Uncertain significance
(Jun 05, 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: SCV004001200.1
First in ClinVar: Jul 08, 2023 Last updated: Jul 08, 2023 |
Comment:
The p.E1039G variant (also known as c.3116A>G), located in coding exon 23 of the MYH7 gene, results from an A to G substitution at nucleotide … (more)
The p.E1039G variant (also known as c.3116A>G), located in coding exon 23 of the MYH7 gene, results from an A to G substitution at nucleotide position 3116. The glutamic acid at codon 1039 is replaced by glycine, an amino acid with similar properties. This alteration has been reported in sudden cardiac death cohorts and hypertrophic cardiomyopathy cohorts; however, clinical details were limited and additional alterations in other cardiac-related genes were identified in some cases (Junttila MJ et al. Circulation, 2018 Jun;137:2716-2726; Lipari M et al. Pol Arch Intern Med, 2020 Feb;130:89-99; Toepfer CN et al. Circulation, 2020 Mar;141:828-842; Vähätalo JH et al. Front Cardiovasc Med, 2021 Jan;8:755062; Sepp R et al. Diagnostics (Basel), 2022 May;12:[ePub ahead of print]). 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
(Apr 18, 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: SCV001350909.3
First in ClinVar: Jun 22, 2020 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces glutamic acid with glycine at codon 1039 of the MYH7 protein. Computational prediction suggests that this variant may have a deleterious … (more)
This missense variant replaces glutamic acid with glycine at codon 1039 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). A functional study using patient-derived tissue has shown that this variant may not impact myosin conformation compared to wild type (PMID: 31983222); the clinical relevance of this observation is not known. This variant has been reported in one individual affected with hypertrophic cardiomyopathy (PMID: 31919335); this individual also carried a pathogenic truncating variant in the MYBPC3 gene. This variant has also been reported in 3 individuals affected with sudden cardiac death and primary myocardial fibrosis (PMID: 29915098, 35087879). This variant has been identified in 27/282848 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)
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Uncertain significance
(Dec 05, 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: SCV000623688.5
First in ClinVar: Dec 26, 2017 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 1039 of the MYH7 protein … (more)
This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 1039 of the MYH7 protein (p.Glu1039Gly). This variant is present in population databases (rs199573700, gnomAD 0.07%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy, MYH7-related conditions (PMID: 31919335, 35087879, 35626289). ClinVar contains an entry for this variant (Variation ID: 426200). 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%. 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
(Nov 02, 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: SCV004832441.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
This missense variant replaces glutamic acid with glycine at codon 1039 of the MYH7 protein. Computational prediction suggests that this variant may have a deleterious … (more)
This missense variant replaces glutamic acid with glycine at codon 1039 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). A functional study using patient-derived tissue has shown that this variant may not impact myosin conformation compared to wild type (PMID: 31983222); the clinical relevance of this observation is not known. This variant has been reported in one individual affected with hypertrophic cardiomyopathy (PMID: 31919335); this individual also carried a pathogenic truncating variant in the MYBPC3 gene. This variant has also been reported in 3 individuals affected with sudden cardiac death and primary myocardial fibrosis (PMID: 29915098, 35087879). This variant has been identified in 27/282848 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: 7
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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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The Genetic Architecture of Hypertrophic Cardiomyopathy in Hungary: Analysis of 242 Patients with a Panel of 98 Genes. | Sepp R | Diagnostics (Basel, Switzerland) | 2022 | PMID: 35626289 |
Genetic Variants Associated With Sudden Cardiac Death in Victims With Single Vessel Coronary Artery Disease and Left Ventricular Hypertrophy With or Without Fibrosis. | Vähätalo JH | Frontiers in cardiovascular medicine | 2022 | PMID: 35087879 |
Myosin Sequestration Regulates Sarcomere Function, Cardiomyocyte Energetics, and Metabolism, Informing the Pathogenesis of Hypertrophic Cardiomyopathy. | Toepfer CN | Circulation | 2020 | PMID: 31983222 |
Identification of a variant hotspot in MYBPC3 and of a novel CSRP3 autosomal recessive alteration in a cohort of Polish patients with hypertrophic cardiomyopathy. | Lipari M | Polish archives of internal medicine | 2020 | PMID: 31919335 |
Primary Myocardial Fibrosis as an Alternative Phenotype Pathway of Inherited Cardiac Structural Disorders. | Junttila MJ | Circulation | 2018 | PMID: 29915098 |
Text-mined citations for rs199573700 ...
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.