ClinVar Genomic variation as it relates to human health
NM_000257.4(MYH7):c.4402G>A (p.Glu1468Lys)
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.4402G>A (p.Glu1468Lys)
Variation ID: 235033 Accession: VCV000235033.16
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 14q11.2 14: 23417270 (GRCh38) [ NCBI UCSC ] 14: 23886479 (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 Jun 5, 2016 May 1, 2024 Mar 4, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000257.4:c.4402G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000248.2:p.Glu1468Lys missense NR_126491.1:n.710C>T non-coding transcript variant NC_000014.9:g.23417270C>T NC_000014.8:g.23886479C>T NG_007884.1:g.23392G>A LRG_384:g.23392G>A LRG_384t1:c.4402G>A - Protein change
- E1468K
- Other names
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- Canonical SPDI
- NC_000014.9:23417269: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
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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 |
3599 | 4856 | |
MHRT | - | - | GRCh38 | - | 776 |
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
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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) |
no assertion criteria provided
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Mar 18, 2014 | RCV000223760.1 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Mar 4, 2024 | RCV000241907.3 | |
Pathogenic (1) |
criteria provided, single submitter
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Nov 27, 2023 | RCV000689327.7 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Sep 14, 2022 | RCV001798726.3 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Oct 31, 2023 | RCV003401157.1 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jan 11, 2023 | RCV003314581.1 |
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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Likely pathogenic
(Sep 14, 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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CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Accession: SCV002042681.2
First in ClinVar: Dec 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Nov 27, 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: SCV000816972.7
First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 1468 of the MYH7 protein … (more)
This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 1468 of the MYH7 protein (p.Glu1468Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 26656175, 27247418, 27737317, 30297972; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 235033). 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%. For these reasons, this variant has been classified as Pathogenic. (less)
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Likely pathogenic
(Mar 04, 2024)
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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: SCV000318193.7
First in ClinVar: Oct 02, 2016 Last updated: May 01, 2024 |
Comment:
The p.E1468K variant (also known as c.4402G>A), located in coding exon 30 of the MYH7 gene, results from a G to A substitution at nucleotide … (more)
The p.E1468K variant (also known as c.4402G>A), located in coding exon 30 of the MYH7 gene, results from a G to A substitution at nucleotide position 4402. The glutamic acid at codon 1468 is replaced by lysine, an amino acid with similar properties. This alteration has been identified in multiple individuals with hypertrophic cardiomyopathy and has been shown to segregate with disease in several families (Bottillo I et al. Gene, 2016 Feb;577:227-35; Mattos BP et al. Arq. Bras. Cardiol., 2016 Sep;107:257-265; Ho CY et al. Circulation, 2018 Oct;138:1387-1398; external communication; Ambry internal data). However, a number of relatives positive for this alteration were reportedly unaffected, suggesting incomplete penetrance. 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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Likely pathogenic
(Jan 11, 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: SCV004014369.1
First in ClinVar: Jul 22, 2023 Last updated: Jul 22, 2023 |
Comment:
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; … (more)
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: 27054166, 27247418, 26656175, 27737317) (less)
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Likely pathogenic
(Oct 31, 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: SCV004122442.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
Variant summary: MYH7 c.4402G>A (p.Glu1468Lys) 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.4402G>A (p.Glu1468Lys) 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 251430 control chromosomes (gnomAD). c.4402G>A has been reported in the literature in multiple individuals affected with Hypertrophic Cardiomyopathy (e.g. Mattos_2016, Bottillo_2016, Homburger_2016, Miller_2019) and has been reported to segregate with the disease phenotype within affected families, although multiple unaffected family members were also reported with the variant, suggesting a reduced penetrance (Mattos_2016). These data indicate that the variant is likely to be associated with disease. 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: 26656175, 30297972, 27247418, 27737317, 31199839). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Three submitters classified the variant as pathogenic/likely pathogenic and one classified it as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic. (less)
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Uncertain significance
(Mar 18, 2014)
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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: SCV000280350.1
First in ClinVar: Jun 05, 2016 Last updated: Jun 05, 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.Glu1468Lys (c.4402G>A) in the MYH7 gene. The variant is novel. This is a non-conservative amino acid change with an acidic polar glutamic acid replaced with a basic polar lysine. The glutamic acid at position 1468 is completely conserved across species. In silico analysis with PolyPhen predicts the variant to be probably damaging with a score of 0.990. Mutation Taster predicts this variant to be disease causing with a score of 56. No other disease-causing variants have been reported at this or nearby codons (+/- 5 codons). The variant was not observed in 200 presumed healthy individuals of Caucasian and African-American ancestry at GeneDx. There is no variation at codon 1468 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6,500 Caucasian and African American individuals (as of 6/20/13. There is also no variant at codon 1468 in 1000 genomes or dbSNP (as of 6/20/13). There is currently insufficient data available on the variant to determine if it causes cardiomyopathy, however the data that is available does suggest it may be pathogenic. Segregation analysis could help clarify the status of this variant. (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 |
Risk Stratification in Hypertrophic Cardiomyopathy. Insights from Genetic Analysis and Cardiopulmonary Exercise Testing. | Magrì D | Journal of clinical medicine | 2020 | PMID: 32481709 |
Defining genotype-phenotype relationships in patients with hypertrophic cardiomyopathy using cardiovascular magnetic resonance imaging. | Miller RJH | PloS one | 2019 | PMID: 31199839 |
Genotype and Lifetime Burden of Disease in Hypertrophic Cardiomyopathy: Insights from the Sarcomeric Human Cardiomyopathy Registry (SHaRe). | Ho CY | Circulation | 2018 | PMID: 30297972 |
Prevalence and Phenotypic Expression of Mutations in the MYH7, MYBPC3 and TNNT2 Genes in Families with Hypertrophic Cardiomyopathy in the South of Brazil: A Cross-Sectional Study. | Mattos BP | Arquivos brasileiros de cardiologia | 2016 | PMID: 27737317 |
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 |
Molecular analysis of sarcomeric and non-sarcomeric genes in patients with hypertrophic cardiomyopathy. | Bottillo I | Gene | 2016 | PMID: 26656175 |
Text-mined citations for rs876657884 ...
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.