ClinVar Genomic variation as it relates to human health
NM_000257.4(MYH7):c.2536G>C (p.Glu846Gln)
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.
Pathogenic(2); Likely pathogenic(3); Uncertain significance(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000257.4(MYH7):c.2536G>C (p.Glu846Gln)
Variation ID: 181194 Accession: VCV000181194.16
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 14q11.2 14: 23424912 (GRCh38) [ NCBI UCSC ] 14: 23894121 (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 24, 2015 May 1, 2024 Nov 30, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000257.4:c.2536G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000248.2:p.Glu846Gln missense NM_000257.3:c.2536G>C NC_000014.9:g.23424912C>G NC_000014.8:g.23894121C>G NG_007884.1:g.15750G>C LRG_384:g.15750G>C LRG_384t1:c.2536G>C P12883:p.Glu846Gln - Protein change
- E846Q
- Other names
- p.E846Q:GAG>CAG
- Canonical SPDI
- NC_000014.9:23424911:C:G
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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
Help
The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00000
The Genome Aggregation Database (gnomAD) 0.00001
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
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
Help
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 |
3598 | 4854 | |
LOC126861898 | - | - | - | GRCh38 | - | 368 |
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
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
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 (1) |
criteria provided, single submitter
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Feb 13, 2013 | RCV000158546.2 | |
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Nov 30, 2023 | RCV000172050.9 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jan 31, 2022 | RCV000253031.3 | |
Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Aug 4, 2022 | RCV001170274.5 |
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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Uncertain significance
(Jun 24, 2013)
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criteria provided, single submitter
Method: research
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Cardiomyopathy, hypertrophic
Affected status: unknown
Allele origin:
unknown
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Biesecker Lab/Clinical Genomics Section, National Institutes of Health
Study: ClinSeq
Accession: SCV000051006.2 First in ClinVar: Jun 08, 2015 Last updated: Sep 14, 2015
Comments (2):
The study set was not selected for affection status in relation to any cancer. Pathogenicity categories were based on literature curation. See Pubmed ID:23861362 for … (more)
The study set was not selected for affection status in relation to any cancer. Pathogenicity categories were based on literature curation. See Pubmed ID:23861362 for details. (less)
Medical sequencing
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Number of individuals with the variant: 1
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Pathogenic
(Feb 13, 2013)
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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: SCV000208481.9
First in ClinVar: Feb 24, 2015 Last updated: Feb 24, 2015 |
Comment:
p.Glu846Gln (GAG>CAG): c.2536 G>C in exon 22 of the MYH7 gene (NM_000257.2). The Glu846Gln mutation in the MYH7 gene has been reported in association with … (more)
p.Glu846Gln (GAG>CAG): c.2536 G>C in exon 22 of the MYH7 gene (NM_000257.2). The Glu846Gln mutation in the MYH7 gene has been reported in association with HCM (Havndrup O et al., 2003; Ho C et al., 2009). Havndrup et al. identified Glu846Gln in one family with three affected individuals who harbored this mutation and it was not observed in 100 control individuals. Other asymptomatic carriers of this mutation were found in younger generations, which the authors suggested was due to reduced penetrance in this family. Mutations in this codon (Glu846Lys) and in nearby codons (Glu844Lys, Arg845Gly, Lys847Glu, Met849Thr) have been reported in association with cardiomyopathy, further supporting the functional importance of this region of the protein. Furthermore, Glu846Gln 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. In summary, Glu846Gln in the MYH7 gene is interpreted as a disease-causing mutation. The variant is found in HCM panel(s). (less)
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Likely pathogenic
(Apr 13, 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: SCV001332837.3
First in ClinVar: May 31, 2020 Last updated: Mar 11, 2023 |
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Pathogenic
(Nov 30, 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: SCV001486522.4
First in ClinVar: Mar 07, 2021 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 846 of the MYH7 protein … (more)
This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 846 of the MYH7 protein (p.Glu846Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of hypertrophic cardiomyopathy (PMID: 12566107, 27532257; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 181194). 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%. 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). For these reasons, this variant has been classified as Pathogenic. (less)
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Likely pathogenic
(Aug 04, 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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Color Diagnostics, LLC DBA Color Health
Accession: SCV004356916.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces glutamic acid with glutamine at codon 846 of the MYH7 protein. Computational prediction suggests that this variant may have deleterious impact … (more)
This missense variant replaces glutamic acid with glutamine at codon 846 of the MYH7 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with at least 7 individuals affected with hypertrophic cardiomyopathy (PMID: PMID: 12566107, 19035361, 20031602, 27532257, communication with external laboratories: ClinVar SCV001486522.2 and SCV000319790.5). It has been shown that this variant segregates with hypertrophic cardiomyopathy in three individuals from one of the families (PMID: 12566107, 19035361). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. (less)
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Likely pathogenic
(Jan 31, 2022)
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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: SCV000319790.7
First in ClinVar: Oct 02, 2016 Last updated: May 01, 2024 |
Comment:
The p.E846Q variant (also known as c.2536G>C), located in coding exon 20 of the MYH7 gene, results from a G to C substitution at nucleotide … (more)
The p.E846Q variant (also known as c.2536G>C), located in coding exon 20 of the MYH7 gene, results from a G to C substitution at nucleotide position 2536. The glutamic acid at codon 846 is replaced by glutamine, 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 alteration has been detected in several individuals with hypertrophic cardiomyopathy (HCM) and was reported to segregate with disease in one family (Havndrup O et al. Cardiovasc Res. 2003;57:347–357; Ho CY et al. Circ Cardiovasc Genet. 2009;2:314-321; Walsh R et al. Genet. Med., 2017 02;19:192-203; Ambry internal data). 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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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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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 |
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. | Richards S | Genetics in medicine : official journal of the American College of Medical Genetics | 2015 | PMID: 25741868 |
Echocardiographic strain imaging to assess early and late consequences of sarcomere mutations in hypertrophic cardiomyopathy. | Ho CY | Circulation. Cardiovascular genetics | 2009 | PMID: 20031602 |
Diagnostic yield, interpretation, and clinical utility of mutation screening of sarcomere encoding genes in Danish hypertrophic cardiomyopathy patients and relatives. | Andersen PS | Human mutation | 2009 | PMID: 19035361 |
Outcome of clinical versus genetic family screening in hypertrophic cardiomyopathy with focus on cardiac beta-myosin gene mutations. | Havndrup O | Cardiovascular research | 2003 | PMID: 12566107 |
An exploratory study of barriers to promoting oral hygiene through carers of elderly people. | Eadie DR | Community dental health | 1992 | PMID: 1486522 |
Translation of bacteriophage T4 mRNA into active lysozyme by a wheat germ cell-free system. | Beck OE | Biochemical and biophysical research communications | 1977 | PMID: 319790 |
Text-mined citations for rs730880748 ...
HelpRecord last updated May 01, 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.