ClinVar Genomic variation as it relates to human health
NM_000257.4(MYH7):c.2221G>C (p.Gly741Arg)
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.2221G>C (p.Gly741Arg)
Variation ID: 14098 Accession: VCV000014098.24
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 14q11.2 14: 23425760 (GRCh38) [ NCBI UCSC ] 14: 23894969 (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 Oct 11, 2015 Feb 20, 2024 Dec 15, 2016 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000257.4:c.2221G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000248.2:p.Gly741Arg missense NC_000014.9:g.23425760C>G NC_000014.8:g.23894969C>G NG_007884.1:g.14902G>C LRG_384:g.14902G>C LRG_384t1:c.2221G>C P12883:p.Gly741Arg - Protein change
- G741R
- Other names
- p.G741R:GGG>CGG
- NM_000257.3(MYH7):c.2221G>C
- Canonical SPDI
- NC_000014.9:23425759:C:G
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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 |
3578 | 4827 |
Conditions - Germline
Condition
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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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Likely pathogenic (2) |
criteria provided, single submitter
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- | RCV000015154.30 | |
Pathogenic (1) |
criteria provided, single submitter
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Nov 23, 2021 | RCV000158522.4 | |
Pathogenic (5) |
reviewed by expert panel
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Dec 15, 2016 | RCV000472342.16 | |
Pathogenic (1) |
criteria provided, single submitter
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Nov 28, 2018 | RCV000621362.3 | |
Pathogenic (1) |
criteria provided, single submitter
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Feb 12, 2019 | RCV001170499.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Sep 26, 2021 | RCV002490371.1 |
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
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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Pathogenic
(Dec 15, 2016)
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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: SCV000564427.5
First in ClinVar: May 29, 2016 Last updated: Dec 11, 2022 |
Comment:
The c.2221G>C (p.Gly741Arg) variant in MYH7 has been reported in >12 individuals with hypertrophic cardiomyopathy (PS4; PMID:8483915; PMID:15563892; PMID:20031618; PMID:15358028; Partners LMM ClinVar SCV000059430.5; SHaRe … (more)
The c.2221G>C (p.Gly741Arg) variant in MYH7 has been reported in >12 individuals with hypertrophic cardiomyopathy (PS4; PMID:8483915; PMID:15563892; PMID:20031618; PMID:15358028; Partners LMM ClinVar SCV000059430.5; SHaRe consortium, PMID: 30297972). This variant has been identified as a de novo occurrence in 1 proband with hypertrophic cardiomyopathy (PM6; PMID:15563892). This variant segregated with disease in 3 affected individuals (PP1; PMID:8483915; Partners LMM ClinVar SCV000059430.5). This variant was absent from large population studies (PM2; http://exac.broadinstitute.org). 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; PMID:27532257). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). A different pathogenic missense variant has been previously identified at this codon which may indicate that this residue is critical to the function of the protein (PM5; c.2221G>T p.Gly741Trp - Variation ID 177665). 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 (PMID:29300372): PS4; PM1; PM2; PM5; PM6; PP1; PP3 (less)
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Pathogenic
(Nov 23, 2021)
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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: SCV000208457.14
First in ClinVar: Feb 24, 2015 Last updated: Mar 04, 2023 |
Comment:
Not observed in large population cohorts (gnomAD); Published functional studies evaluating the contractile properties of single slow-twitch muscle fibers from patients with this variant demonstrate … (more)
Not observed in large population cohorts (gnomAD); Published functional studies evaluating the contractile properties of single slow-twitch muscle fibers from patients with this variant demonstrate that G741R results in decreased maximum velocity of fiber shortening and decreased isometric force generation, suggesting this variant has a damaging effect on the protein (Lankford et al., 1995); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 7731997, 24093860, 27532257, 27476098, 31006259, 33642254, 15563892, 20031618, 8483915, 15358028, 12707239, 28246639, 27247418, 24111713, 29300372, 24704860, 32710294, 25935763, 32894683, 7883988) (less)
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Pathogenic
(Nov 09, 2023)
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criteria provided, single submitter
Method: clinical testing
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Hypertrophic cardiomyopathy
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000546223.9
First in ClinVar: Apr 17, 2017 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 741 of the MYH7 protein (p.Gly741Arg). … (more)
This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 741 of the MYH7 protein (p.Gly741Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 8483915, 12707239, 15358028, 15563892, 20031618, 24093860, 24111713, 24704860). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 14098). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MYH7 protein function with a positive predictive value of 95%. This variant disrupts the p.Gly741 amino acid residue in MYH7. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8533830, 15856146). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
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Likely pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Hypertrophic cardiomyopathy 1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Laboratory of Genetics and Molecular Cardiology, University of São Paulo
Study: Sarcomeric Human Cardiomyopathy Registry (ShaRe)
Accession: SCV000256140.1 First in ClinVar: Oct 11, 2015 Last updated: Oct 11, 2015 |
Number of individuals with the variant: 2
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Likely pathogenic
(Oct 16, 2015)
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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: SCV000059430.6
First in ClinVar: May 03, 2013 Last updated: Aug 14, 2019 |
Comment:
The p.Gly741Arg variant has been reported in >10 individuals with HCM, occurred de novo in one of them, and segregated with disease in 3 affected … (more)
The p.Gly741Arg variant has been reported in >10 individuals with HCM, occurred de novo in one of them, and segregated with disease in 3 affected relatives from 2 families (Fananapazir 1993, Malinchik 1997, Richard 2003, Van Driest 2004, So ng 2005, Kaski 2009, LMM unpublished data). It has not been identified in large population studies. This variant was predicted to be pathogenic using a computat ional tool clinically validated by our laboratory. This tool's pathogenic predic tion is estimated to be correct 94% of the time (Jordan 2011). In summary, altho ugh additional studies are required to fully establish its clinical significance , this variant is likely pathogenic. (less)
Number of individuals with the variant: 6
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Pathogenic
(Jun 14, 2017)
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criteria provided, single submitter
Method: research
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Hypertrophic cardiomyopathy
Affected status: yes
Allele origin:
germline
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Agnes Ginges Centre for Molecular Cardiology, Centenary Institute
Accession: SCV000996368.2
First in ClinVar: Nov 02, 2019 Last updated: Jan 13, 2020 |
Comment:
The MYH7 Gly741Arg (c.2221G>C) has been reported in more than 10 unrelated HCM probands and has been found to cosegregate in a few cases (see … (more)
The MYH7 Gly741Arg (c.2221G>C) has been reported in more than 10 unrelated HCM probands and has been found to cosegregate in a few cases (see literature). Song L, et al., (2005), reported 1 HCM where the variant arose de novo. We identified this variant in 1 HCM proband of Middle Eastern descent, with a strong family history of disease in the family, however genetic testing was only possible for one affected sibling who was also found to harbour the variant. The variant is absent in the 1000 genomes project (http://www.1000genomes.org/), as well as the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/). Computational tools, SIFT, PolyPhen-2, PolyPhen-HCM and MutationTaster predict this variant to be deleterious. Furthermore functional studies suggest that the variant results in decreased velocity of shortening and reduced isometric force generation (Lankford EB, et al., 1995). In a large HCM population study Walsh et al., showed that MYH7 variants identified in HCM cases were found to cluster between amino acids 181- 937 (2017), this implies that variants in this region are likely to cause a HCM phenotype. Furthermore variant located in the converter region of MYH7 (amino acids 709-777) are predicted to result in worse outcomes (Garcia-Giustiniani D, et al., 2015). Interestingly, a different rare variant at this position (Gly741Trp) has also been classified as pathogenic, suggesting that an amino acid substitution at this site may not be tolerated. In summary based on this evidence we classify MYH7 Gly741Arg as 'Pathogenic'. (less)
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Pathogenic
(Feb 12, 2019)
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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: SCV001333082.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
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Pathogenic
(Mar 31, 2016)
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criteria provided, single submitter
Method: clinical testing
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Cardiomyopathy, hypertrophic
Affected status: unknown
Allele origin:
germline
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Knight Diagnostic Laboratories, Oregon Health and Sciences University
Accession: SCV001449021.1
First in ClinVar: Dec 12, 2020 Last updated: Dec 12, 2020 |
Number of individuals with the variant: 1
Sex: female
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Pathogenic
(Nov 28, 2018)
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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: SCV000740146.4
First in ClinVar: Apr 14, 2018 Last updated: Nov 29, 2022 |
Comment:
The p.G741R pathogenic mutation (also known as c.2221G>C), located in coding exon 18 of the MYH7 gene, results from a G to C substitution at … (more)
The p.G741R pathogenic mutation (also known as c.2221G>C), located in coding exon 18 of the MYH7 gene, results from a G to C substitution at nucleotide position 2221. The glycine at codon 741 is replaced by arginine, an amino acid with dissimilar properties. This alteration, and a different nucleotide substitution (c.2221G>A) resulting in the same amino acid change were reported to segregate with disease in families with hypertrophic cardiomyopathy (HCM) including a reported de novo occurrence (Fananapazir L, Proc. Natl. Acad. Sci. U.S.A. 1993 May; 90(9):3993-7; Montag J et al. J. Muscle Res. Cell. Motil. 2017 Aug;38(3-4):291-302). The p.G741R alteration has been reported in multiple additional HCM cohorts (Richard P et al. Circulation. 2003;107(17):2227-32; Van Driest SL et al. J Am Coll Cardiol. 2004;44(3):602-10; Song L et al. Clin Chim Acta. 2005;351(1-2):209-16; Kindel SJ et al. J Card Fail. 2012;18(5):396-403; Marsiglia JD et al. Am Heart J. 2013;166(4):775-82; Berge KE et al. Clin Genet 2014;86(4):355-60). In addition, another alteration involving the same amino acid (p.G741W, c.2221G>T) has also been reported in association with HCM (Arai S et al. Am J Med Genet. 1995;58:267-76). 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
(Sep 26, 2021)
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criteria provided, single submitter
Method: clinical testing
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MYH7-related skeletal myopathy
Myosin storage myopathy Hypertrophic cardiomyopathy 1 Myopathy, myosin storage, autosomal recessive Congenital myopathy 4A, autosomal dominant Myosin storage myopathy Dilated cardiomyopathy 1S
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002793972.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(May 01, 1993)
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no assertion criteria provided
Method: literature only
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CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 1
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000035411.2
First in ClinVar: Apr 04, 2013 Last updated: Nov 10, 2016 |
Comment on evidence:
In 1 of 3 patients with hypertrophic cardiomyopathy (CMH1; 192600) and the G741R mutation, Fananapazir et al. (1993) found microscopic changes of central core disease … (more)
In 1 of 3 patients with hypertrophic cardiomyopathy (CMH1; 192600) and the G741R mutation, Fananapazir et al. (1993) found microscopic changes of central core disease on soleus muscle biopsy. (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 |
Intrinsic MYH7 expression regulation contributes to tissue level allelic imbalance in hypertrophic cardiomyopathy. | Montag J | Journal of muscle research and cell motility | 2017 | PMID: 29101517 |
Biophysical properties of human β-cardiac myosin with converter mutations that cause hypertrophic cardiomyopathy. | Kawana M | Science advances | 2017 | PMID: 28246639 |
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 |
Phenotype and prognostic correlations of the converter region mutations affecting the β myosin heavy chain. | García-Giustiniani D | Heart (British Cardiac Society) | 2015 | PMID: 25935763 |
Rare variants in genes encoding MuRF1 and MuRF2 are modifiers of hypertrophic cardiomyopathy. | Su M | International journal of molecular sciences | 2014 | PMID: 24865491 |
Abnormal cardiac formation in hypertrophic cardiomyopathy: fractal analysis of trabeculae and preclinical gene expression. | Captur G | Circulation. Cardiovascular genetics | 2014 | PMID: 24704860 |
Genetics of hypertrophic cardiomyopathy in Norway. | Berge KE | Clinical genetics | 2014 | PMID: 24111713 |
Screening of MYH7, MYBPC3, and TNNT2 genes in Brazilian patients with hypertrophic cardiomyopathy. | Marsiglia JD | American heart journal | 2013 | PMID: 24093860 |
Pediatric cardiomyopathy: importance of genetic and metabolic evaluation. | Kindel SJ | Journal of cardiac failure | 2012 | PMID: 22555271 |
Junctophilin-2 expression silencing causes cardiocyte hypertrophy and abnormal intracellular calcium-handling. | Landstrom AP | Circulation. Heart failure | 2011 | PMID: 21216834 |
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 of sarcomere protein gene mutations in preadolescent children with hypertrophic cardiomyopathy. | Kaski JP | Circulation. Cardiovascular genetics | 2009 | PMID: 20031618 |
Expression patterns of cardiac myofilament proteins: genomic and protein analysis of surgical myectomy tissue from patients with obstructive hypertrophic cardiomyopathy. | Theis JL | Circulation. Heart failure | 2009 | PMID: 19808356 |
Prevalence of cardiac beta-myosin heavy chain gene mutations in patients with hypertrophic cardiomyopathy. | Perrot A | Journal of molecular medicine (Berlin, Germany) | 2005 | PMID: 15856146 |
Mutations profile in Chinese patients with hypertrophic cardiomyopathy. | Song L | Clinica chimica acta; international journal of clinical chemistry | 2005 | PMID: 15563892 |
Comprehensive analysis of the beta-myosin heavy chain gene in 389 unrelated patients with hypertrophic cardiomyopathy. | Van Driest SL | Journal of the American College of Cardiology | 2004 | PMID: 15358028 |
Hypertrophic cardiomyopathy: distribution of disease genes, spectrum of mutations, and implications for a molecular diagnosis strategy. | Richard P | Circulation | 2003 | PMID: 12707239 |
N232S, G741R and D778G beta-cardiac myosin mutants, implicated in familial hypertrophic cardiomyopathy, do not disrupt myofibrillar organisation in cultured myotubes. | Miller G | FEBS letters | 2000 | PMID: 11196015 |
Isometric tension and mutant myosin heavy chain content in single skeletal myofibers from hypertrophic cardiomyopathy patients. | Malinchik S | Journal of molecular and cellular cardiology | 1997 | PMID: 9140824 |
Missense mutation of the beta-cardiac myosin heavy-chain gene in hypertrophic cardiomyopathy. | Arai S | American journal of medical genetics | 1995 | PMID: 8533830 |
Abnormal contractile properties of muscle fibers expressing beta-myosin heavy chain gene mutations in patients with hypertrophic cardiomyopathy. | Lankford EB | The Journal of clinical investigation | 1995 | PMID: 7883988 |
Structural interpretation of the mutations in the beta-cardiac myosin that have been implicated in familial hypertrophic cardiomyopathy. | Rayment I | Proceedings of the National Academy of Sciences of the United States of America | 1995 | PMID: 7731997 |
Missense mutations in the beta-myosin heavy-chain gene cause central core disease in hypertrophic cardiomyopathy. | Fananapazir L | Proceedings of the National Academy of Sciences of the United States of America | 1993 | PMID: 8483915 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/380d3ce8-4982-4df6-9bc5-6f4f7f75301c | - | - | - | - |
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Text-mined citations for rs121913632 ...
HelpRecord last updated Feb 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.