ClinVar Genomic variation as it relates to human health
NM_000257.4(MYH7):c.5401G>A (p.Glu1801Lys)
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.5401G>A (p.Glu1801Lys)
Variation ID: 43069 Accession: VCV000043069.13
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 14q11.2 14: 23415153 (GRCh38) [ NCBI UCSC ] 14: 23884362 (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 Aug 8, 2014 Feb 14, 2024 Dec 15, 2016 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000257.4:c.5401G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000248.2:p.Glu1801Lys missense NC_000014.9:g.23415153C>T NC_000014.8:g.23884362C>T NG_007884.1:g.25509G>A LRG_384:g.25509G>A LRG_384t1:c.5401G>A LRG_384p1:p.Glu1801Lys - Protein change
- E1801K
- Other names
- p.E1801K:GAG>AAG
- NM_000257.3(MYH7):c.5401G>A
- Canonical SPDI
- NC_000014.9:23415152: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 |
3578 | 4827 |
Conditions - Germline
Condition
Help
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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Pathogenic (2) |
criteria provided, single submitter
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Dec 13, 2017 | RCV000132759.17 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Feb 1, 2017 | RCV000158700.11 | |
Pathogenic (1) |
criteria provided, single submitter
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Nov 25, 2014 | RCV000211834.11 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 20, 2015 | RCV000207999.8 | |
Likely pathogenic (1) |
reviewed by expert panel
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Dec 15, 2016 | RCV000487436.9 | |
Pathogenic (1) |
criteria provided, single submitter
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Sep 17, 2023 | RCV000699484.11 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jun 10, 2022 | RCV003320085.8 |
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
Help
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
(Dec 15, 2016)
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reviewed by expert panel
Method: curation
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Primary dilated cardiomyopathy
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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ClinGen Cardiomyopathy Variant Curation Expert Panel
Accession: SCV000564459.5
First in ClinVar: Apr 28, 2017 Last updated: Dec 11, 2022 |
Comment:
The c.5401G>A (p.Glu1801Lys) variant in MYH7 has been reported in 4 individuals with dilated cardiomyopathy, one of whom had additional myopathy features (PS4_Supporting; PMID:19477645; Partners … (more)
The c.5401G>A (p.Glu1801Lys) variant in MYH7 has been reported in 4 individuals with dilated cardiomyopathy, one of whom had additional myopathy features (PS4_Supporting; PMID:19477645; Partners LMM ClinVar SCV000059616.5). Additionally, in two of the probands with dilated cardiomyopathy, the variant occurred de novo (PM6; Partners LMM ClinVar SCV000059616.5). This variant was absent from large population studies (PM2; http://exac.broadinstitute.org). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for dilated cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (PMID:29300372): PM2; PM6; PP3; PS4_ Supporting (less)
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Pathogenic
(Nov 25, 2014)
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criteria provided, single submitter
Method: clinical testing
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Primary dilated cardiomyopathy
Neuromuscular disease (Autosomal dominant inheritance)
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000059616.5
First in ClinVar: May 03, 2013 Last updated: Jun 05, 2016 |
Comment:
The p.Glu1801Lys variant in MYH7 has been reported in 1 individual with early on set distal myopathy and late onset DCM (Udd 2009) as well … (more)
The p.Glu1801Lys variant in MYH7 has been reported in 1 individual with early on set distal myopathy and late onset DCM (Udd 2009) as well as 1 individual with e arly onset distal myopathy and HCM (Lamont 2014). The p.Glu1801Lys variant has a lso been identified by our laboratory in three infants with DCM and occurred de novo in two of them (LMM unpublished data). Additionally, this variant was abse nt from large population studies. Glutamic acid (Glu) is highly conserved in mam mals and across evolutionarily distant species and the change to lysine (Lys) wa s predicted to be pathogenic using a computational tool, which was validated by our laboratory using a set of cardiomyopathy variants with well-established clin ical significance. This tool's pathogenic prediction is estimated to be correct 94% of the time (Jordan 2011). In summary, this variant meets our criteria to be classified as pathogenic for Laing distal myopathy with cardiomyopathy in an au tosomal dominant manner (http://www.partners.org/personalizedmedicine/LMM) base d upon absence from controls and multiple de novo occurrences. (less)
Number of individuals with the variant: 3
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Pathogenic
(Sep 17, 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: SCV000828197.4
First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024 |
Comment:
This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein … (more)
This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. 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: 43069). This missense change has been observed in individuals with autosomal dominant MYH7-related conditions (PMID: 19477645, 24503780, 24664454, 27532257, 28855170). It has also been observed to segregate with disease in related individuals. This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 1801 of the MYH7 protein (p.Glu1801Lys). (less)
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Pathogenic
(Aug 20, 2015)
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criteria provided, single submitter
Method: clinical testing
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Left ventricular noncompaction cardiomyopathy
Affected status: yes
Allele origin:
germline
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Blueprint Genetics
Accession: SCV000264100.2
First in ClinVar: Feb 27, 2016 Last updated: Feb 27, 2016 |
Number of individuals with the variant: 1
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Likely pathogenic
(Feb 01, 2017)
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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: SCV000208635.10
First in ClinVar: Feb 24, 2015 Last updated: Mar 08, 2017 |
Comment:
The E1801K likely pathogenic variant in the MYH7 gene has been reported in a Moldavian family with early onset distal myopathy and later onset, severe … (more)
The E1801K likely pathogenic variant in the MYH7 gene has been reported in a Moldavian family with early onset distal myopathy and later onset, severe DCM (Udd et al., 2009). Lamont et al. (2014) also found E1801K in two members of an Israeli family with distal muscle weakness, and the proband was diagnosed with HCM at age 23. Ruggiero et al. (2015) identified the E1801K variant in three members of an Italian family with cardiomyopathy and distal myopathy. Additionally, E1801K has been observed in two infants tested at GeneDx for DCM. In each case, parental testing did not identify the E1801K variant, suggesting that these events occurred de novo. Similarly, the Laboratory for Molecular Medicine reports that E1801K has been observed in three infants with DCM tested at their laboratory, and was de novo in two of these cases (ClinVar SCV000059616.4; Landrum et al.,2016). E1801K results in a non-conservative amino acid substitution at a position that is conserved across species. In silico analysis predicts E1801K is probably damaging to the protein structure/function. Furthermore, E1801K was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Although a variant at this same residue (E1801G) has been reported in association with cardiomyopathy (Stenson et al., 2014), the clinical significance of this variant has not been definitively determined. Therefore, this variant is likely pathogenic. (less)
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Pathogenic
(Dec 13, 2017)
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criteria provided, single submitter
Method: clinical testing
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MYH7-related skeletal myopathy
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München
Accession: SCV000680306.1
First in ClinVar: Feb 08, 2018 Last updated: Feb 08, 2018 |
Sex: male
Tissue: blood
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Likely pathogenic
(Jun 10, 2022)
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criteria provided, single submitter
Method: clinical testing
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Myosin storage myopathy
Affected status: yes
Allele origin:
germline
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MGZ Medical Genetics Center
Accession: SCV002580115.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 |
Number of individuals with the variant: 1
Sex: female
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Pathogenic
(Jan 01, 2013)
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no assertion criteria provided
Method: clinical testing
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Myopathy, distal, 1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Neurogenetics Laboratory, Royal Perth Hospital
Accession: SCV000119910.1
First in ClinVar: Aug 08, 2014 Last updated: Aug 08, 2014 |
Number of individuals with the variant: 2
Family history: Yes
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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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Adaptation and validation of the ACMG/AMP variant classification framework for MYH7-associated inherited cardiomyopathies: recommendations by ClinGen's Inherited Cardiomyopathy Expert Panel. | Kelly MA | Genetics in medicine : official journal of the American College of Medical Genetics | 2018 | PMID: 29300372 |
A Wide and Specific Spectrum of Genetic Variants and Genotype-Phenotype Correlations Revealed by Next-Generation Sequencing in Patients with Left Ventricular Noncompaction. | Wang C | Journal of the American Heart Association | 2017 | PMID: 28855170 |
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 mutations widen the phenotypic spectrum of slow skeletal/β-cardiac myosin (MYH7) distal myopathy. | Lamont PJ | Human mutation | 2014 | PMID: 24664454 |
The landscape of genetic variation in dilated cardiomyopathy as surveyed by clinical DNA sequencing. | Pugh TJ | Genetics in medicine : official journal of the American College of Medical Genetics | 2014 | PMID: 24503780 |
Myosinopathies: pathology and mechanisms. | Tajsharghi H | Acta neuropathologica | 2013 | PMID: 22918376 |
165th ENMC International Workshop: distal myopathies 6-8th February 2009 Naarden, The Netherlands. | Udd B | Neuromuscular disorders : NMD | 2009 | PMID: 19477645 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/7c729fe3-84ef-4174-a0d8-c152b6dc76d7 | - | - | - | - |
Text-mined citations for rs397516248 ...
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.