ClinVar Genomic variation as it relates to human health
NM_000257.4(MYH7):c.3578G>A (p.Arg1193His)
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.3578G>A (p.Arg1193His)
Variation ID: 42965 Accession: VCV000042965.20
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 14q11.2 14: 23419993 (GRCh38) [ NCBI UCSC ] 14: 23889202 (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 Feb 28, 2024 Dec 22, 2021 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000257.4:c.3578G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000248.2:p.Arg1193His missense NC_000014.9:g.23419993C>T NC_000014.8:g.23889202C>T NG_007884.1:g.20669G>A LRG_384:g.20669G>A LRG_384t1:c.3578G>A - Protein change
- R1193H
- Other names
- p.R1193H:CGC>CAC
- NM_000257.3(MYH7):c.3578G>A
- NM_000257.4(MYH7):c.3578G>A
- Canonical SPDI
- NC_000014.9:23419992: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.
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00001
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
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 |
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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Jan 16, 2020 | RCV000158611.11 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jul 24, 2017 | RCV000627139.11 | |
Likely pathogenic (2) |
reviewed by expert panel
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Dec 22, 2021 | RCV001059046.13 | |
Uncertain significance (1) |
criteria provided, single submitter
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Feb 1, 2021 | RCV001449662.12 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Dec 7, 2023 | RCV003485529.1 |
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
(Dec 22, 2021)
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reviewed by expert panel
Method: curation
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Hypertrophic cardiomyopathy
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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ClinGen Cardiomyopathy Variant Curation Expert Panel
Accession: SCV000564445.5
First in ClinVar: Apr 29, 2017 Last updated: Dec 25, 2021 |
Comment:
The NM_000257.4(MYH7):c.3578G>A (p.Arg1193His) variant has been identified in at least 9 individuals with DCM, including 1 individual with an additional variant in another gene that … (more)
The NM_000257.4(MYH7):c.3578G>A (p.Arg1193His) variant has been identified in at least 9 individuals with DCM, including 1 individual with an additional variant in another gene that may contribute to their disease and 1 individual with DCM and a bicuspid aortic valve (PS4_Moderate; GeneDx pers. comm.; LMM pers. comm.; OMGL pers. comm.). This variant also segregated in 5 affected relatives with DCM from 4 families (PP1_Moderate; LMM pers. comm.; OMGL pers. comm.). Additionally, this variant has also been reported in 1 individual with LVNC, 1 individual with non-ischemic cardiomyopathy and 1 individual with biventricular dilation with ventricular tachycardia (GeneDx pers. comm., Invitae pers. comm., LMM pers. comm.). This variant was absent from large population studies (PM2; gnomAD v2.1.1, http://gnomad.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. ACMG/AMP Criteria applied: PS4_Moderate, PP1_Moderate, PM2, PP3. (less)
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Uncertain significance
(Feb 01, 2021)
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criteria provided, single submitter
Method: clinical testing
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not specified
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000059509.7
First in ClinVar: May 03, 2013 Last updated: May 29, 2021 |
Comment:
Variant classified as Uncertain Significance - Favor Pathogenic. The p.Arg1193His variant in MYH7 has been identified in 7 Caucasian individuals with DCM and segregated with … (more)
Variant classified as Uncertain Significance - Favor Pathogenic. The p.Arg1193His variant in MYH7 has been identified in 7 Caucasian individuals with DCM and segregated with disease in 4 affected relatives, including one obligate carrier, and has been reported in one individual with HCM (Lakdawala 2012 PMID: 22464770, Walsh 2017 PMID: 27532257, LMM data). It has also been identified in 0.01% (1/104518) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. A different variant (p.Arg1193Ser) at this position has been reported in 1 individual with DCM and segregated with disease in 3 affected family members (Villard 2005 PMID: 15769782), supporting that a change at this position may not be tolerated. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PS4_Moderate, PM2_Supporting, PP1, PP3. (less)
Number of individuals with the variant: 10
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Pathogenic
(Nov 15, 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: SCV001223650.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 28, 2024 |
Comment:
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) … (more)
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. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg1193 amino acid residue in MYH7. Other variant(s) that disrupt this residue have been observed in individuals with MYH7-related conditions (PMID: 15769782), which suggests that this may be a clinically significant amino acid residue. ClinVar contains an entry for this variant (Variation ID: 42965). This missense change has been observed in individuals with clinical features of dilated cardiomyopathy or hypertrophic cardiomyopathy (PMID: 22464770, 27532257; Invitae; external communication). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs397516187, gnomAD 0.001%). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1193 of the MYH7 protein (p.Arg1193His). (less)
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Likely pathogenic
(Jul 24, 2017)
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criteria provided, single submitter
Method: clinical testing
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Primary familial dilated cardiomyopathy
Affected status: yes
Allele origin:
germline
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Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute
Accession: SCV000747955.1
First in ClinVar: May 21, 2018 Last updated: May 21, 2018 |
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Uncertain significance
(Jan 16, 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: SCV000208546.11
First in ClinVar: Feb 24, 2015 Last updated: Jul 14, 2019 |
Comment:
Reported in association with HCM and DCM (Lakdawala et al., 2012; Walsh et al., 2017); Reported in ClinVar as a variant of uncertain significance by … (more)
Reported in association with HCM and DCM (Lakdawala et al., 2012; Walsh et al., 2017); Reported in ClinVar as a variant of uncertain significance by the ClinGen Inherited Cardiomyopathy Variant Curation Expert Panel (ClinVar Variant ID# 42965; SCV000564445.4; Landrum et al., 2016); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 29300372, 22464770, 27532257) (less)
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Likely pathogenic
(Dec 07, 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: SCV004241894.1
First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024 |
Comment:
Variant summary: MYH7 c.3578G>A (p.Arg1193His) results in a non-conservative amino acid change located in the Myosin tail domain (IPR002928) of the encoded protein sequence. Five … (more)
Variant summary: MYH7 c.3578G>A (p.Arg1193His) results in a non-conservative amino acid change located in the Myosin tail domain (IPR002928) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.4e-06 in 236944 control chromosomes (gnomAD). c.3578G>A has been reported in the literature in individuals affected with Hypertrophic Cardiomyopathy or Dilated Cardiomyopathy (Lakdawala_2012, Pugh_2014, Walsh_2017). 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: 22464770, 24503780, 27532257, 29300372). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. One submitter classified it as pathogenic, two (including a ClinGen expert panel) classified it as likely pathogenic, and two classified it as uncertain significance. Based on the evidence outlined above, the variant was classified as likely 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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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 |
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 |
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 |
Genetic testing for dilated cardiomyopathy in clinical practice. | Lakdawala NK | Journal of cardiac failure | 2012 | PMID: 22464770 |
Development and validation of a computational method for assessment of missense variants in hypertrophic cardiomyopathy. | Jordan DM | American journal of human genetics | 2011 | PMID: 21310275 |
Mutation screening in dilated cardiomyopathy: prominent role of the beta myosin heavy chain gene. | Villard E | European heart journal | 2005 | PMID: 15769782 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/da44d8c5-f133-4882-8a5a-1a6c85b2e7b3 | - | - | - | - |
Text-mined citations for rs397516187 ...
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.