ClinVar Genomic variation as it relates to human health
NM_000257.4(MYH7):c.1208G>T (p.Arg403Leu)
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.1208G>T (p.Arg403Leu)
Variation ID: 14101 Accession: VCV000014101.13
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 14q11.2 14: 23429278 (GRCh38) [ NCBI UCSC ] 14: 23898487 (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 May 29, 2016 May 1, 2024 Sep 11, 2020 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000257.4:c.1208G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000248.2:p.Arg403Leu missense NC_000014.9:g.23429278C>A NC_000014.8:g.23898487C>A NG_007884.1:g.11384G>T LRG_384:g.11384G>T LRG_384t1:c.1208G>T LRG_384p1:p.Arg403Leu P12883:p.Arg403Leu - Protein change
- R403L
- Other names
- p.R403L:CGG>CTG
- Canonical SPDI
- NC_000014.9:23429277:C:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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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
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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
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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 |
3599 | 4856 |
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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Pathogenic (1) |
no assertion criteria provided
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Dec 1, 1993 | RCV000015157.22 | |
Pathogenic (2) |
criteria provided, single submitter
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May 28, 2020 | RCV000158679.7 | |
Pathogenic (1) |
criteria provided, single submitter
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Sep 11, 2020 | RCV001381369.6 | |
Pathogenic (1) |
criteria provided, single submitter
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Jul 23, 2020 | RCV002345243.2 |
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
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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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Pathogenic
(May 28, 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: SCV000208614.12
First in ClinVar: Feb 24, 2015 Last updated: Jul 24, 2021 |
Comment:
Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; … (more)
Not observed in large population cohorts (Lek et al., 2016); 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: 30847666, 31006259, 27532257, 15386449, 12707239, 18227814, 24566549, 7731997, 7848420, 8254035) (less)
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Pathogenic
(Sep 11, 2020)
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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: SCV001579735.4
First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine with leucine at codon 403 of the MYH7 protein (p.Arg403Leu). The arginine residue is highly conserved and there is a … (more)
This sequence change replaces arginine with leucine at codon 403 of the MYH7 protein (p.Arg403Leu). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and leucine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 8254035, 27532257). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 14101). This variant is found within a region of MYH7 between codons 181 and 937 that contains the majority of the myosin head domain. Missense variants in this region have been shown to be significantly overrepresented in individuals with hypertrophic cardiomyopathy (PMID: 27532257). This variant disrupts the p.Arg403 amino acid residue in MYH7. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10725281, 23751935, 18029407, 10882745). 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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Pathogenic
(Jul 23, 2020)
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criteria provided, single submitter
Method: clinical testing
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Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV002648499.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.R403L pathogenic mutation (also known as c.1208G>T), located in coding exon 11 of the MYH7 gene, results from a G to T substitution at … (more)
The p.R403L pathogenic mutation (also known as c.1208G>T), located in coding exon 11 of the MYH7 gene, results from a G to T substitution at nucleotide position 1208. The arginine at codon 403 is replaced by leucine, an amino acid with dissimilar properties, and is located in the head domain. This variant has been reported in several unrelated individuals with hypertrophic cardiomyopathy (HCM), and has been reported to segregate with disease in families (Dausse E et al. J. Clin. Invest., 1993 Dec;92:2807-13; al-Mahdawi S et al. Br Heart J, 1994 Aug;72:105-11; Santos S et al. BMC Med. Genet. 2012 Mar;13:17; Walsh R et al. Genet. Med., 2017 02;19:192-203; Cui H et al. Orphanet J Rare Dis. 2019 11;14(1):252; Norrish G et al. Circulation, 2019 07;140:184-192). In addition, other pathogenic variants affecting this codon (p.R403Q, c.1208G>A and p.R403W, c.1207C>T) have also been reported in association with HCM (Dausse E et al. J. Clin. Invest., 1993 Dec;92:2807-13; Van Driest SL et al. J. Am. Coll. Cardiol., 2004 Aug;44:602-10). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
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Pathogenic
(Dec 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: SCV000035414.2
First in ClinVar: Apr 04, 2013 Last updated: Nov 10, 2016 |
Comment on evidence:
In 2 French pedigrees with familial hypertrophic cardiomyopathy (CMH1; 192600), Dausse et al. (1993) performed linkage analysis using 2 microsatellite markers located in the MYH7 … (more)
In 2 French pedigrees with familial hypertrophic cardiomyopathy (CMH1; 192600), Dausse et al. (1993) performed linkage analysis using 2 microsatellite markers located in the MYH7 gene, as well as 4 highly informative markers that mapped to the 14q11-q12 region. Linkage to the markers was found in pedigree 720, but results were not conclusive for pedigree 730. Haplotype of 6 markers allowed identification of affected individuals and of some unaffected subjects who were carrying the disease gene. Two novel missense mutations were identified in exon 13 by direct sequencing: arg403 to leu (R403L) and arg403 to trp (R403W) in families 720 and 730, respectively. The arg403-to-leu mutation was associated with incomplete penetrance, a high incidence of sudden deaths and severe cardiac events, whereas the consequences of the arg403-to-trp mutation appeared to be less severe. Codon 403 of the MYH7 gene appears, therefore, to be a hotspot for mutations causing CMH. The first mutation identified in this disorder involved codon 403 (160760.0001). (less)
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Likely pathogenic
(Jun 16, 2015)
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no assertion criteria provided
Method: clinical testing
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Not provided
Affected status: not provided
Allele origin:
germline
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Stanford Center for Inherited Cardiovascular Disease, Stanford University
Accession: SCV000280296.1
First in ClinVar: May 29, 2016 Last updated: May 29, 2016 |
Comment:
Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case … (more)
Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Arg403Leu (c.1208G>T) in MYH7 Based on the data reviewed below we consider this variant likely disease-associated. The variant has been seen in at least 3 unrelated cases of HCM with strong segregation data. The variant was first reported by Dausse et al (1993) in a large kindred in which linkage studies including 11 affected relatives pointed towards MYH7. Sequencing of MYH7 identified p.Arg403Leu and its presence was confirmed in 6 affected individuals. A subsequent publication that included some of the same authors reported an additional family that appears to be distinct from the initial report (Al-Mahdawi et al 1994). Three affected individuals and one obligate carrier carried p.Arg403Leu. Richard et al (2003) reported the variant in one individual with HCM. In silico analysis with PolyPhen-2 predicts the variant to be probably damaging. The arginine at codon 403 is conserved across species, as are neighboring amino acids. Other variants have been reported in association with disease at this codon (p.Arg403Gln and p.Arg403Trp, both very likely disease cuausing) and nearby codons (p.Arg404Leu, p.Arg404Met, p.Arg406Met, p.Arg407Val). Moolman et al (1993) noted that there is a CpG doublet at codon 403 which may likely makes it susceptible to mutation. In total the variant has not been seen in 5150 published controls and publicly available population datsets. There is no variation at codon 403 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~5000 Caucasian and African American individuals (as of 1/14/2012). There is also no variation at this codon listed in 1000 genomes (as of 1/14/2012). p.Arg403Gln is not listed in dbSNP (as of 1/14/2012). The variant was not observed in the following published control samples: 50 (Al-Mahdawi et al 1994), 100 (Richard et al 2003). (less)
Number of individuals with the variant: 3
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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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mTOR pathway in human cardiac hypertrophy caused by LEOPARD syndrome: a different role compared with animal models? | Cui H | Orphanet journal of rare diseases | 2019 | PMID: 31722741 |
Yield of Clinical Screening for Hypertrophic Cardiomyopathy in Child First-Degree Relatives. | Norrish G | Circulation | 2019 | PMID: 31006259 |
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 |
Creatine kinase adenosine triphosphate and phosphocreatine energy supply in a single kindred of patients with hypertrophic cardiomyopathy. | Abraham MR | The American journal of cardiology | 2013 | PMID: 23751935 |
High resolution melting: improvements in the genetic diagnosis of hypertrophic cardiomyopathy in a Portuguese cohort. | Santos S | BMC medical genetics | 2012 | PMID: 22429680 |
Troponin T and beta-myosin mutations have distinct cardiac functional effects in hypertrophic cardiomyopathy patients without hypertrophy. | Revera M | Cardiovascular research | 2008 | PMID: 18029407 |
Prenatal molecular diagnosis in hypertrophic cardiomyopathy: report of the first case. | Charron P | Prenatal diagnosis | 2004 | PMID: 15386449 |
Functional consequences of mutations in the smooth muscle myosin heavy chain at sites implicated in familial hypertrophic cardiomyopathy. | Yamashita H | The Journal of biological chemistry | 2000 | PMID: 10882745 |
Temporal repolarization lability in hypertrophic cardiomyopathy caused by beta-myosin heavy-chain gene mutations. | Atiga WL | Circulation | 2000 | PMID: 10725281 |
The electrocardiogram is a more sensitive indicator than echocardiography of hypertrophic cardiomyopathy in families with a mutation in the MYH7 gene. | al-Mahdawi S | British heart journal | 1994 | PMID: 7848420 |
Familial hypertrophic cardiomyopathy. Microsatellite haplotyping and identification of a hot spot for mutations in the beta-myosin heavy chain gene. | Dausse E | The Journal of clinical investigation | 1993 | PMID: 8254035 |
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Text-mined citations for rs121913624 ...
HelpRecord last updated May 01, 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.