ClinVar Genomic variation as it relates to human health
NM_000257.4(MYH7):c.2360G>A (p.Arg787His)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000257.4(MYH7):c.2360G>A (p.Arg787His)
Variation ID: 42900 Accession: VCV000042900.44
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 14q11.2 14: 23425345 (GRCh38) [ NCBI UCSC ] 14: 23894554 (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 Dec 6, 2014 May 1, 2024 Apr 27, 2021 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000257.4:c.2360G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000248.2:p.Arg787His missense NC_000014.9:g.23425345C>T NC_000014.8:g.23894554C>T NG_007884.1:g.15317G>A LRG_384:g.15317G>A LRG_384t1:c.2360G>A P12883:p.Arg787His - Protein change
- R787H
- Other names
- NM_000257.3(MYH7):c.2360G>A
- Canonical SPDI
- NC_000014.9:23425344: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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0.00020 (T)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00022
Trans-Omics for Precision Medicine (TOPMed) 0.00007
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
1000 Genomes Project 30x 0.00016
The Genome Aggregation Database (gnomAD) 0.00006
1000 Genomes Project 0.00020
The Genome Aggregation Database (gnomAD), exomes 0.00020
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
Help
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 |
3634 | 4908 | |
LOC126861898 | - | - | - | GRCh38 | - | 371 |
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 (5) |
criteria provided, multiple submitters, no conflicts
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Jul 15, 2019 | RCV000035789.31 | |
Uncertain significance (2) |
criteria provided, single submitter
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Jun 27, 2017 | RCV000148708.14 | |
Likely benign (1) |
criteria provided, single submitter
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Jun 9, 2022 | RCV000250929.14 | |
Likely benign (1) |
criteria provided, single submitter
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Apr 27, 2017 | RCV000348947.14 | |
Likely benign (2) |
reviewed by expert panel
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Apr 27, 2021 | RCV000313839.22 | |
Likely benign (1) |
criteria provided, single submitter
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Apr 27, 2017 | RCV000354671.14 | |
Likely benign (1) |
criteria provided, single submitter
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Jun 14, 2016 | RCV000392220.14 | |
Benign/Likely benign (3) |
criteria provided, multiple submitters, no conflicts
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Aug 22, 2023 | RCV000584813.18 | |
Likely benign (2) |
criteria provided, multiple submitters, no conflicts
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Oct 19, 2020 | RCV000776332.13 | |
Likely benign (4) |
criteria provided, multiple submitters, no conflicts
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Dec 21, 2022 | RCV001705651.14 | |
Likely benign (1) |
criteria provided, single submitter
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Apr 27, 2017 | RCV003320055.8 | |
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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 benign
(Apr 27, 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
FDA Recognized Database
Accession: SCV000564429.5 First in ClinVar: Oct 05, 2015 Last updated: Sep 10, 2021 |
Comment:
The c.2360G>A (p.Arg787His) variant in MYH7 has been identified in 0.10% (FAF 95% CI; 41/30616) of South Asian chromosomes in gnomAD v2.1.1 (https://gnomad.broadinstitute.org), which is … (more)
The c.2360G>A (p.Arg787His) variant in MYH7 has been identified in 0.10% (FAF 95% CI; 41/30616) of South Asian chromosomes in gnomAD v2.1.1 (https://gnomad.broadinstitute.org), which is a high enough frequency to be classified as likely benign based on thresholds defined by the ClinGen Inherited Cardiomyopathy Expert Panel (BS1; Kelly 2018 PMID:29300372). Allowing a variant to reach a likely benign classification based on BS1 alone represents a revision of the original ACMG/AMP framework by ClinGen’s Sequence Variant Interpretation Working Group (Tavtigian 2018 PMID: 29300386). Additionally, while this variant lies in the head region of the protein (aa 181-937) and missense variants in this region are statistically more likely to be disease-associated (PM1; Walsh 2017 PMID:27532257), this pathogenic evidence code (PM1) was not considered to be in conflict with a likely benign conclusion. In summary, this variant meets criteria to be classified as likely benign for cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): BS1, PM1. (less)
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Uncertain significance
(Apr 05, 2015)
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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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Genetic Services Laboratory, University of Chicago
Accession: SCV000248114.1
First in ClinVar: Oct 05, 2015 Last updated: Oct 05, 2015 |
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Uncertain significance
(Dec 09, 2016)
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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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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000604365.1
First in ClinVar: Sep 28, 2017 Last updated: Sep 28, 2017 |
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Likely benign
(Jun 09, 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: SCV000318690.7
First in ClinVar: Oct 02, 2016 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
(Jun 05, 2013)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000059440.6
First in ClinVar: May 03, 2013 Last updated: Aug 14, 2019 |
Comment:
The Arg787His variant has been reported in 7 probands (6 with HCM and 1 with DCM ), has been detected by our laboratory in 4 … (more)
The Arg787His variant has been reported in 7 probands (6 with HCM and 1 with DCM ), has been detected by our laboratory in 4 additional individuals with HCM. The majority of these individuals were of Indian or Arabic descent (Richard 2003, Y u 2005, Laredo 2006, Boda 2009, Rai 2009, Purushotham 2010; LMM unpublished data ). Three of 11 probands (2: LMM, 1: Laredo 2006) carried a second variant suffi cient to explain their disease. The variant was present in 1/4406 African Americ an chromosomes from a broad population screened by the NHLBI Exome Sequencing pr oject (http://evs.gs.washington.edu/EVS) but absent from 600 were race-matched c hromosomes (Purushotham 2010) and 600 additional chromosomes across several stud ies (Richard 2003, Yu 2005, Laredo 2006, Boda 2009, Rai 2009). Another variant a t the same position (Arg787Cys) has been reported in individuals with HCM (Morit a 2008, Garcia-Castro 2009); however, the affected amino acid (arginine) is only moderately conserved in evolution, suggesting that a change may be tolerated or be milder. A milder effect was also suspected by Purushotham 2010 who detected the variant in 2 affected individuals but also 8 asymptomatic relatives. Of not e, one of these families had a history of sudden death including the son of an i ndividual who tested negative for the Arg787His variant. While a phenocopy cann ot be ruled out this possible non-segregation raises concern regarding the patho genicity of the Arg787His variant. In summary, the data for this variant is some what conflicting and additional studies are needed to clarify its role in diseas e. (less)
Number of individuals with the variant: 6
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Likely benign
(Oct 19, 2020)
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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: SCV002042269.1
First in ClinVar: Jan 01, 2022 Last updated: Jan 01, 2022 |
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Benign
(Aug 22, 2023)
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criteria provided, single submitter
Method: clinical testing
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Hypertrophic cardiomyopathy 1
Affected status: unknown
Allele origin:
germline
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Mendelics
Accession: SCV001139415.2
First in ClinVar: Jan 09, 2020 Last updated: Aug 25, 2023 |
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Likely benign
(Dec 21, 2022)
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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: SCV004237856.1
First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024 |
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Likely benign
(Jun 14, 2016)
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criteria provided, single submitter
Method: clinical testing
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Left Ventricular Noncompaction Cardiomyopathy
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000386159.2
First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016 |
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Uncertain significance
(Jun 27, 2017)
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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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Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute
Accession: SCV000740370.1
First in ClinVar: Dec 06, 2014 Last updated: Dec 06, 2014 |
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Likely benign
(Oct 05, 2018)
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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: SCV000911684.1
First in ClinVar: May 20, 2019 Last updated: May 20, 2019 |
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Likely benign
(Apr 27, 2017)
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criteria provided, single submitter
Method: clinical testing
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Hypertrophic cardiomyopathy 1
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000386157.3
First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
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Likely benign
(Apr 27, 2017)
|
criteria provided, single submitter
Method: clinical testing
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MYH7-related skeletal myopathy
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000386158.3
First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
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Likely benign
(Apr 27, 2017)
|
criteria provided, single submitter
Method: clinical testing
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Dilated cardiomyopathy 1S
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000386155.3
First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
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Likely benign
(Apr 27, 2017)
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criteria provided, single submitter
Method: clinical testing
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Myosin storage myopathy
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV000386156.3
First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
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Uncertain significance
(Jul 15, 2019)
|
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: SCV001360966.1
First in ClinVar: Jun 22, 2020 Last updated: Jun 22, 2020 |
Comment:
Variant summary: MYH7 c.2360G>A (p.Arg787His) results in a non-conservative amino acid change located in the Myosin head, motor domain of the encoded protein sequence. Three … (more)
Variant summary: MYH7 c.2360G>A (p.Arg787His) results in a non-conservative amino acid change located in the Myosin head, motor domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0002 in 251472 control chromosomes, predominantly at a frequency of 0.0013 within the South Asian subpopulation in the gnomAD database. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 1.039 fold of the estimated maximal expected allele frequency for a pathogenic variant in MYH7 causing Cardiomyopathy phenotype (0.0013), suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. c.2360G>A has been reported in the literature in multiple individuals affected with Cardiomyopathy. However, the variant has also been observed in multiple families that showed lack of cosegregation with disease including unaffected individuals with the variant and affected individuals without the variant (Purushotham_2010, Laredo_2006). In addition, the variant has been observed to co-occur with other pathogenic variants, MYBPC3 c.3641G>A, p.W1214X; MYH7, I736T), providing supporting evidence for a benign role. A functional study, Sequeira_2013, indicates the variant to have higher Ca 2+ sensitivity and low phosphorylation of protein kinase A targets compared to donors, along with length-dependent activation being significantly smaller. Ten ClinVar submissions (evaluation after 2014) cite the variant five times as likely benign, while five other submissions including the expert panel, ClinGen, cite the variant as uncertain signfiicance. In addition, another variant affecting the same codon, R787C, has been reported in affected individuals suggesting the location could be important for protein function. Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
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Likely benign
(Mar 10, 2017)
|
criteria provided, single submitter
Method: research
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Hypertrophic cardiomyopathy 1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Agnes Ginges Centre for Molecular Cardiology, Centenary Institute
Accession: SCV000692500.2
First in ClinVar: Feb 25, 2018 Last updated: Dec 11, 2022 |
Comment:
The MYH7 Arg787His variant occurs in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/) at a frequency of 0.02%. In silico tools (SIFT, PolyPhen-HCM, MutationTaster) are in … (more)
The MYH7 Arg787His variant occurs in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/) at a frequency of 0.02%. In silico tools (SIFT, PolyPhen-HCM, MutationTaster) are in support of a benign role. The MHY7 Arg787His variant was identified in a HCM proband with no family history of disease. The proband also harbours 2 additional MYBPC3 variants (p.Ala693Val & p.Arg817Gly) that are likely contributing to the disease phenotype. A second individual with non-diagnostic hypertrophy was also identified with this variant. Based on the high frequency in the general population and in silico tool predicting a benign effect, we classify MYH7 Arg787His as "likely benign". (less)
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Likely benign
(Feb 04, 2021)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000208466.14
First in ClinVar: Feb 24, 2015 Last updated: Mar 04, 2023 |
Comment:
This variant is associated with the following publications: (PMID: 17125710, 29343710, 20086309, 12707239, 31006259, 20664766, 20433692, 21959974, 22957257, 23299917, 25228707, 25637381, 27247418, 28518168, 30731207, 29300372, … (more)
This variant is associated with the following publications: (PMID: 17125710, 29343710, 20086309, 12707239, 31006259, 20664766, 20433692, 21959974, 22957257, 23299917, 25228707, 25637381, 27247418, 28518168, 30731207, 29300372, 30847666, 31638223) (less)
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Likely benign
(Jan 31, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Hypertrophic cardiomyopathy
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000557944.8
First in ClinVar: Dec 06, 2016 Last updated: Feb 14, 2024 |
|
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Uncertain significance
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics, Academic Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001919667.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021 |
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Uncertain significance
(Jun 01, 2014)
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no assertion criteria provided
Method: research
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Cardiomyopathy, hypertrophic
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
CSER _CC_NCGL, University of Washington
Study: ESP 6500 variant annotation
Accession: SCV000190438.1 First in ClinVar: Dec 06, 2014 Last updated: Dec 06, 2014
Comment:
Variants classified for the Actionable exomic incidental findings in 6503 participants: challenges of variant classification manuscript
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|
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Uncertain significance
(Jan 29, 2014)
|
no assertion criteria provided
Method: clinical testing
|
not specified
Affected status: not provided
Allele origin:
germline
|
Stanford Center for Inherited Cardiovascular Disease, Stanford University
Accession: SCV000280321.1
First in ClinVar: Oct 05, 2015 Last updated: Oct 05, 2015 |
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. MYH7 p.Arg787His We consider this a variant of uncertain significance, likely disease causing, based on the co-occurrence of another pathogenic variant in several of the cases with multi-gene sequencing and the possible failure to segregate in one family. The variant has been seen in at least 9 unrelated cases of cardiomyopathy (not including the patient). Three patients had another variant sufficient to explain their disease. Five of the other cases had insufficient sequencing to determine if another variant was present. There is weak segregation data in two families, though in one of them there is potential for failure to segregate with insufficient information available. Richard P et al., 2003 first described this variant in a European individual with HCM. They sequenced 9 genes (MYH7, MYBPC3, TNNI3, TNNT2, MYL2, MYL3, TPM1, ACTC and TNNC1) in 197 unrelated index cases with HCM. Patients were recruited from France and most of them were of European origin. No details regarding this patient's phenotype was given. Yu et al (2005) observed the variant in one of 150 patients with HCM from their Australian cohort. They reported only on analysis of MYH7. Laredo et al (2006) reported this variant in a 43 year old Spanish female, who also harbored p.Ile736Thr variant in the MYH7 gene (which we classify as likely disease causing). They sequenced MYH7 in 128 patients with HCM to compare the phenotypes of those with and without mutations in MYH7. The patient who harbored this variant in addition to the p.Ile736Thr variant in MYH7 was a female diagnosed at age 43 with a maximum thickness of 30mm and asymmetric hypertrophic morphology. The patient's mother was diagnosed with HCM at age 43 and had undergone a myectomy and died from heart failure at age 69. It appears that the father tested negative for both variants. The patient's sons both inherited only the p.Ile736Thr variant, revealing that these variants were in trans. Her eldest son had some hypertrophy with maximal thickness of 11mm at age 21. Her youngest son had maximal thickness of 13mm with asymmetric hypertrophy at age 16. None of the studied family members had just p.Arg787His. Boda et al (2009) observed the variant in one of 100 idiopathic DCM cases in their Indian cohort. They analyzed MYH7, TNNI3, ACTC. Rai et al (2009) observed the variant in one of 69 patients with HCM in their Indian cohort. They only analyzed MYH7. Purushotham et al. (2010) reported this variant in two unrelated Indian patients with HCM. The authors sequenced exons 3-23 of the MYH7 gene and all exons of the MYBPC3 gene. The authors did not sequence other genes in the patients identified to carry the p.Arg787His variant. In each family there were two affected first degree relatives who carry the variant. Of note, in one of these families there was an "uninvestigated sudden death" in the child of someone who tested negative for the variant, suggesting a possible failure to segregate. This variant is located in exon 21 of the MYH7 gene. In silico analysis with PolyPhen-2 predicts the variant to be possibly damaging. The arginine at codon 787 is conserved across species, as are neighboring amino acids. Other variants have been reported in association with disease at this codon (p.Arg787Cys) and nearby codons (Ser782Asn; Arg783His, Arg793Gln). Purushotham and colleagues presented some functional data which suggested that this substitution is not tolerated. Sequence and structure analysis of the MYH7 mutation revealed that the mutant protein might be compromised in its ability to bind essential light chain efficiently. The authors suggested that the MYH7 p.Arg787His variant may result in mild clinical symptoms similar to other mutations that occur in the neck region of the protein. In total the variant has been seen in 1 of 7003 published controls and individuals from publicly available population datasets. The variant was reported online in 0 of 4300 Caucasian individuals and 1 of 2203 African-American individuals in the NHLBI Exome Sequencing Project dataset (as of 2/6/14). The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. Note that other variants with strong evidence for pathogenicity have been seen at similar frequencies in this dataset so this does not necessarily rule out pathogenicity (Pan et al 2012). Note that this dataset does not match the patient's ancestry (Chinese) or the ancestry of about half of the cases (Indian). There is also no variation at this codon listed in dbSNP or 1000 genomes (as of 2/5/14). The variant was not observed in the following published control samples: 100 control individuals (Richard et al 2003), 100 control individuals (Purushotham et al 2010), 100 control individuals (Yu et al 2005), 100 control individuals (Boda et al 2009), 100 control individuals (Rai et al 2009). (less)
Number of individuals with the variant: 10
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Genome Diagnostics Laboratory, University Medical Center Utrecht
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001928253.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021 |
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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 |
---|---|---|---|---|
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 |
Using high-resolution variant frequencies to empower clinical genome interpretation. | Whiffin N | Genetics in medicine : official journal of the American College of Medical Genetics | 2017 | PMID: 28518168 |
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 |
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 |
Patient Outcomes From a Specialized Inherited Arrhythmia Clinic. | Adler A | Circulation. Arrhythmia and electrophysiology | 2016 | PMID: 26743238 |
Actionable exomic incidental findings in 6503 participants: challenges of variant classification. | Amendola LM | Genome research | 2015 | PMID: 25637381 |
Novel genotype-phenotype associations demonstrated by high-throughput sequencing in patients with hypertrophic cardiomyopathy. | Lopes LR | Heart (British Cardiac Society) | 2015 | PMID: 25351510 |
Malignant effects of multiple rare variants in sarcomere genes on the prognosis of patients with hypertrophic cardiomyopathy. | Wang J | European journal of heart failure | 2014 | PMID: 25132132 |
Perturbed length-dependent activation in human hypertrophic cardiomyopathy with missense sarcomeric gene mutations. | Sequeira V | Circulation research | 2013 | PMID: 23508784 |
New population-based exome data are questioning the pathogenicity of previously cardiomyopathy-associated genetic variants. | Andreasen C | European journal of human genetics : EJHG | 2013 | PMID: 23299917 |
A low prevalence of MYH7/MYBPC3 mutations among familial hypertrophic cardiomyopathy patients in India. | Bashyam MD | Molecular and cellular biochemistry | 2012 | PMID: 21959974 |
The MYH7 p.R787H mutation causes hypertrophic cardiomyopathy in two unrelated families. | Purushotham G | Experimental and clinical cardiology | 2010 | PMID: 20664766 |
Novel mutations in beta-myosin heavy chain, actin and troponin-I genes associated with dilated cardiomyopathy in Indian population. | Boda U | Journal of genetics | 2009 | PMID: 20086309 |
[Mutations in sarcomeric genes MYH7, MYBPC3, TNNT2, TNNI3, and TPM1 in patients with hypertrophic cardiomyopathy]. | García-Castro M | Revista espanola de cardiologia | 2009 | PMID: 19150014 |
Genotype phenotype correlations of cardiac beta-myosin heavy chain mutations in Indian patients with hypertrophic and dilated cardiomyopathy. | Rai TS | Molecular and cellular biochemistry | 2009 | PMID: 18953637 |
Shared genetic causes of cardiac hypertrophy in children and adults. | Morita H | The New England journal of medicine | 2008 | PMID: 18403758 |
[Beta-myosin heavy-chain gene mutations in patients with hypertrophic cardiomyopathy]. | Laredo R | Revista espanola de cardiologia | 2006 | PMID: 17125710 |
Denaturing high performance liquid chromatography: high throughput mutation screening in familial hypertrophic cardiomyopathy and SNP genotyping in motor neurone disease. | Yu B | Journal of clinical pathology | 2005 | PMID: 15858117 |
Hypertrophic cardiomyopathy: distribution of disease genes, spectrum of mutations, and implications for a molecular diagnosis strategy. | Richard P | Circulation | 2003 | PMID: 12707239 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/de961e5a-a5f1-47f5-abee-524b09b41cc0 | - | - | - | - |
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Text-mined citations for rs376754645 ...
HelpRecord last updated Oct 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.