ClinVar Genomic variation as it relates to human health
NM_000257.4(MYH7):c.3158G>A (p.Arg1053Gln)
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.3158G>A (p.Arg1053Gln)
Variation ID: 155814 Accession: VCV000155814.23
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 14q11.2 14: 23422267 (GRCh38) [ NCBI UCSC ] 14: 23891476 (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 27, 2016 Feb 28, 2024 Nov 30, 2021 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000257.4:c.3158G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000248.2:p.Arg1053Gln missense NC_000014.9:g.23422267C>T NC_000014.8:g.23891476C>T NG_007884.1:g.18395G>A LRG_384:g.18395G>A LRG_384t1:c.3158G>A - Protein change
- R1053Q
- Other names
- p.R1053Q:CGG>CAG
- NM_000257.3(MYH7):c.3158G>A
- NM_000257.4(MYH7):c.3158G>A
- Canonical SPDI
- NC_000014.9:23422266: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.
Trans-Omics for Precision Medicine (TOPMed) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00006
Exome Aggregation Consortium (ExAC) 0.00007
The Genome Aggregation Database (gnomAD) 0.00008
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
Help
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 |
3417 | 4600 |
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 (1) |
criteria provided, single submitter
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Nov 20, 2015 | RCV000143923.4 | |
Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jun 9, 2023 | RCV000158590.8 | |
Pathogenic (4) |
reviewed by expert panel
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Nov 30, 2021 | RCV000529602.13 | |
Pathogenic (1) |
criteria provided, single submitter
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May 27, 2022 | RCV000621026.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Jun 28, 2022 | RCV003149914.2 |
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
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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
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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Pathogenic
(Nov 30, 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: SCV000564442.5
First in ClinVar: Apr 29, 2017 Last updated: Dec 25, 2021 |
Comment:
The NM_000257.4(MYH7):c.3158G>A (p.Arg1053Gln) variant in MYH7 has been reported in >35 individuals with hypertrophic cardiomyopathy (HCM), a large proportion of which are of Finnish ancestry … (more)
The NM_000257.4(MYH7):c.3158G>A (p.Arg1053Gln) variant in MYH7 has been reported in >35 individuals with hypertrophic cardiomyopathy (HCM), a large proportion of which are of Finnish ancestry (PS4; Kärkkäinen 2004 PMID:15556047; Jääskeläinen 2014 PMID:24888384; Walsh 2017 PMID:27532257; Ambry pers. comm.; GeneDx pers. comm., Invitae pers. comm.; LMM pers. comm.; OMGL pers. comm.). This variant segregated with disease in >15 affected individuals with HCM in 9 families (PP1_Moderate; Kärkkäinen 2004 PMID:15556047; GeneDx pers. comm.; OMGL pers. comm.). This variant was identified in 0.040% (FAF 95% CI; 16/25124) of Finnish chromosomes in gnomAD v2.1.1 (http://gnomad.broadinstitute.org), but was absent from other populations and is an established Finnish founder variant. 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 pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4; PP1_Strong; PM2; PP3. (less)
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Pathogenic
(Nov 20, 2015)
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criteria provided, single submitter
Method: clinical testing
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Primary familial hypertrophic cardiomyopathy
Affected status: yes
Allele origin:
germline
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Blueprint Genetics
Accession: SCV000188800.4
First in ClinVar: Sep 07, 2014 Last updated: Feb 27, 2016 |
Number of individuals with the variant: 13
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Pathogenic
(May 08, 2014)
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criteria provided, single submitter
Method: clinical testing
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Hypertrophic cardiomyopathy
(Autosomal dominant inheritance)
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000203956.4
First in ClinVar: Jan 31, 2015 Last updated: Mar 04, 2019 |
Comment:
The Arg1053Gln variant in MYH7 has been reported in 1 individual with a dilated left ventrical and impaired systolic function, and was present in 5 … (more)
The Arg1053Gln variant in MYH7 has been reported in 1 individual with a dilated left ventrical and impaired systolic function, and was present in 5 additional a ffected family members with clinical features of septal HCM (Karkkainen 2004). I n addition, it has been identified by our laboratory in 1 individual with HCM an d family history of SCD. The variant was absent from large population studies. Arganine (Arg) at position 1053 is highly conserved in evolution and the change to glutamine (Gln) was predicted to be pathogenic using a computational tool cli nically validated by our laboratory. This tool's pathogenic prediction is estima ted to be correct 94% of the time (Jordan 2011). In summary, this variant meets our criteria to be classified as pathogenic (http://pcpgm.partners.org/LMM) bas ed upon segregation studies and absence from controls. (less)
Number of individuals with the variant: 1
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Likely pathogenic
(Aug 06, 2021)
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criteria provided, single submitter
Method: clinical testing
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Hypertrophic Cardiomyopathy
Affected status: no
Allele origin:
germline
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National Institute of Allergy and Infectious Diseases - Centralized Sequencing Program, National Institutes of Health
Accession: SCV002522168.1
First in ClinVar: Jun 03, 2022 Last updated: Jun 03, 2022 |
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Pathogenic
(May 27, 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: SCV000739917.4
First in ClinVar: Apr 14, 2018 Last updated: Nov 29, 2022 |
Comment:
The p.R1053Q pathogenic mutation (also known as c.3158G>A), located in coding exon 23 of the MYH7 gene, results from a G to A substitution at … (more)
The p.R1053Q pathogenic mutation (also known as c.3158G>A), located in coding exon 23 of the MYH7 gene, results from a G to A substitution at nucleotide position 3158. The arginine at codon 1053 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been reported in numerous individuals with hypertrophic cardiomyopathy (HCM), including segregating with disease in one family (Kärkkäinen S, Eur. J. Heart Fail. 2004 Dec; 6(7):861-8; Millat G et al. Eur J Med Genet Jul;53:261-7; Walsh R et al. Genet Med, 2017 02;19:192-203; Kelly MA et al. Genet Med, 2018 03;20:351-359; Jääskeläinen P et al. ESC Heart Fail, 2019 Apr;6:436-445; Marschall C et al. Cardiovasc Diagn Ther, 2019 Oct;9:S292-S298; Costain G et al. JAMA Netw Open, 2020 09;3:e2018109; Yoshinaga M et al. Circ J, 2021 12;86:118-127; Hathaway J et al. BMC Cardiovasc Disord, 2021 03;21:126). This alteration has also been described as a founder mutation in a Finnish HCM cohort, accounting for approximately 5-8% of MYH7 variants detected (Jääskeläinen P et al. Ann. Med., 2014 Sep;46:424-9; Jääskeläinen P et al. ESC Heart Fail, 2019 Apr;6:436-445). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
Number of individuals with the variant: 1
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Pathogenic
(Jun 28, 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: SCV003838109.1
First in ClinVar: Mar 11, 2023 Last updated: Mar 11, 2023 |
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Pathogenic
(Jun 09, 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: SCV000208525.13
First in ClinVar: Feb 24, 2015 Last updated: Jun 17, 2023 |
Comment:
Reported in Finnish patients with HCM and described as the third most common mutation encountered in Finnish patients with HCM (Jskelinen et al., 2014); In … (more)
Reported in Finnish patients with HCM and described as the third most common mutation encountered in Finnish patients with HCM (Jskelinen et al., 2014); 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: 15556047, 30775854, 27247418, 27532257, 29300372, 21310275, 33673806, 31737537, 24888384, 20624503, 35626289, 35753512) (less)
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Likely pathogenic
(Nov 29, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV003834096.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
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Pathogenic
(Jan 08, 2024)
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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: SCV000623690.7
First in ClinVar: Dec 26, 2017 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1053 of the MYH7 protein (p.Arg1053Gln). … (more)
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1053 of the MYH7 protein (p.Arg1053Gln). This variant is present in population databases (rs587782962, gnomAD 0.07%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 15556047, 20624503, 24888384, 27247418, 27460395, 27532257). It is commonly reported in individuals of Finnish ancestry (PMID: 15556047, 20624503, 24888384, 27247418, 27460395, 27532257). ClinVar contains an entry for this variant (Variation ID: 155814). 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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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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Electrocardiographic Diagnosis of Hypertrophic Cardiomyopathy in the Pre- and Post-Diagnostic Phases in Children and Adolescents. | Yoshinaga M | Circulation journal : official journal of the Japanese Circulation Society | 2021 | PMID: 34615813 |
Diagnostic yield of genetic testing in a heterogeneous cohort of 1376 HCM patients. | Hathaway J | BMC cardiovascular disorders | 2021 | PMID: 33673806 |
Genome Sequencing as a Diagnostic Test in Children With Unexplained Medical Complexity. | Costain G | JAMA network open | 2020 | PMID: 32960281 |
Variant panorama in 1,385 index patients and sensitivity of expanded next-generation sequencing panels in arrhythmogenic disorders. | Marschall C | Cardiovascular diagnosis and therapy | 2019 | PMID: 31737537 |
Genetic basis and outcome in a nationwide study of Finnish patients with hypertrophic cardiomyopathy. | Jääskeläinen P | ESC heart failure | 2019 | PMID: 30775854 |
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 |
Current perspectives in hypertrophic cardiomyopathy with the focus on patients in the Finnish population: a review. | Kuusisto J | Annals of medicine | 2016 | PMID: 27460395 |
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 |
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 |
A new common mutation in the cardiac beta-myosin heavy chain gene in Finnish patients with hypertrophic cardiomyopathy. | Jääskeläinen P | Annals of medicine | 2014 | PMID: 24888384 |
Development of a high resolution melting method for the detection of genetic variations in hypertrophic cardiomyopathy. | Millat G | Clinica chimica acta; international journal of clinical chemistry | 2010 | PMID: 20800588 |
Prevalence and spectrum of mutations in a cohort of 192 unrelated patients with hypertrophic cardiomyopathy. | Millat G | European journal of medical genetics | 2010 | PMID: 20624503 |
Two novel mutations in the beta-myosin heavy chain gene associated with dilated cardiomyopathy. | Kärkkäinen S | European journal of heart failure | 2004 | PMID: 15556047 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/da96f339-d77d-4caf-afe3-768754b0efca | - | - | - | - |
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Text-mined citations for rs587782962 ...
HelpRecord last updated Mar 17, 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.