ClinVar Genomic variation as it relates to human health
NM_000257.4(MYH7):c.3551A>T (p.Gln1184Leu)
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.
Uncertain significance(4); Likely benign(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.3551A>T (p.Gln1184Leu)
Variation ID: 181226 Accession: VCV000181226.11
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 14q11.2 14: 23420020 (GRCh38) [ NCBI UCSC ] 14: 23889229 (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 2, 2016 May 1, 2024 Nov 30, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000257.4:c.3551A>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000248.2:p.Gln1184Leu missense NC_000014.9:g.23420020T>A NC_000014.8:g.23889229T>A NG_007884.1:g.20642A>T LRG_384:g.20642A>T LRG_384t1:c.3551A>T - Protein change
- Q1184L
- Other names
- p.Q1184L:CAG>CTG
- Canonical SPDI
- NC_000014.9:23420019:T:A
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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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0.00040 (A)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
Exome Aggregation Consortium (ExAC) 0.00005
The Genome Aggregation Database (gnomAD), exomes 0.00005
1000 Genomes Project 30x 0.00031
1000 Genomes Project 0.00040
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
Help
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 |
3599 | 4856 |
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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Uncertain significance (2) |
criteria provided, single submitter
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Feb 15, 2023 | RCV000223885.3 | |
Uncertain significance (1) |
criteria provided, single submitter
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May 26, 2017 | RCV000766447.1 | |
Uncertain significance (1) |
criteria provided, single submitter
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Aug 13, 2022 | RCV000794278.5 | |
Likely benign (1) |
criteria provided, single submitter
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Sep 16, 2020 | RCV002453547.2 | |
Uncertain significance (1) |
criteria provided, single submitter
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Nov 30, 2023 | RCV003998357.2 |
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
(May 26, 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: SCV000208545.10
First in ClinVar: Feb 24, 2015 Last updated: Jun 02, 2016 |
Comment:
A variant of uncertain significance has been identified in the MYH7 gene. The Q1184L variant has not been published as pathogenic or been reported as … (more)
A variant of uncertain significance has been identified in the MYH7 gene. The Q1184L variant has not been published as pathogenic or been reported as benign to our knowledge. This variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The Q1184L variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. However, this variant lacks observation in a significant number of affected individuals, segregation data, and functional evidence, which would further clarify its pathogenicity. (less)
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Uncertain significance
(Aug 13, 2022)
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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: SCV000933674.5
First in ClinVar: Aug 14, 2019 Last updated: Feb 07, 2023 |
Comment:
This sequence change replaces glutamine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 1184 of the MYH7 protein (p.Gln1184Leu). … (more)
This sequence change replaces glutamine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 1184 of the MYH7 protein (p.Gln1184Leu). This variant is present in population databases (rs546586969, gnomAD 0.06%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 30297972). ClinVar contains an entry for this variant (Variation ID: 181226). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). 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
(Feb 15, 2023)
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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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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV003844758.1
First in ClinVar: Mar 26, 2023 Last updated: Mar 26, 2023 |
Comment:
Variant summary: MYH7 c.3551A>T (p.Gln1184Leu) results in a non-conservative amino acid change located in the Myosin tail domain (IPR002928) of the encoded protein sequence. Four … (more)
Variant summary: MYH7 c.3551A>T (p.Gln1184Leu) results in a non-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 allele was found at a frequency of 4.6e-05 in 215646 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in MYH7 causing Cardiomyopathy (4.6e-05 vs 0.0013), allowing no conclusion about variant significance. c.3551A>T has been reported in the literature in individuals affected with hypertrophic cardiomyopathy, while it was also identified in two asymptomatic family members related to one of the affected individuals (e.g., Ho_2018, Tran-Vu_2019). These reports do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 with conflicting assessments; two laboratories classified the variant as uncertain significance and one laboratory classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
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Uncertain Significance
(Nov 30, 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: SCV004814394.1
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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Number of individuals with the variant: 3
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Likely benign
(Sep 16, 2020)
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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: SCV002617315.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of … (more)
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
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Uncertain significance
(Mar 03, 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: SCV000280340.1
First in ClinVar: Jun 02, 2016 Last updated: Jun 02, 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.Gln1184Leu in the MYH7 gene at exon 27. This variant is novel and has not been reported as a disease-causing mutation or as a benign polymorphism. This is a non-conserved amino acid substitution which changes an uncharged polar glutamine to a nonpolar leucine residue. In silico analysis with PolyPhen-2 predicts the variant to be possibly damaging with a score of 0.689. Mutation Taster predicts this change to be damaging with a score of 113. The Glutamine at codon 1184 is conserved across species, as are neighboring amino acids. A variant at codon 1193 (p.Arg1193His) has been reported in HGMD in association with cardiomyopathy (Stendon P et al., 2009). In total the variant has not been seen in ~6000 individuals from publicly available population datasets. There is no variation at codon 1184 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6000 Caucasian and African American individuals (as of 5/31/13). Note that this dataset does not match the patient's ancestry. There is also no variation at this codon listed in dbSNP or 1000 genomes (as of 5/31/13). (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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Presence of Hypertrophic Cardiomyopathy Related Gene Mutations and Clinical Manifestations in Vietnamese Patients With Hypertrophic Cardiomyopathy. | Tran Vu MT | Circulation journal : official journal of the Japanese Circulation Society | 2019 | PMID: 31308319 |
Genotype and Lifetime Burden of Disease in Hypertrophic Cardiomyopathy: Insights from the Sarcomeric Human Cardiomyopathy Registry (SHaRe). | Ho CY | Circulation | 2018 | PMID: 30297972 |
Text-mined citations for rs546586969 ...
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.