ClinVar Genomic variation as it relates to human health
NM_000258.3(MYL3):c.281G>A (p.Arg94His)
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_000258.3(MYL3):c.281G>A (p.Arg94His)
Variation ID: 31777 Accession: VCV000031777.16
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p21.31 3: 46860702 (GRCh38) [ NCBI UCSC ] 3: 46902192 (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 Apr 4, 2013 Feb 20, 2024 Apr 28, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000258.3:c.281G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000249.1:p.Arg94His missense NC_000003.12:g.46860702C>T NC_000003.11:g.46902192C>T NG_007555.2:g.26468G>A LRG_395:g.26468G>A LRG_395t1:c.281G>A LRG_395p1:p.Arg94His - Protein change
- R94H
- Other names
- p.R94H:CGT>CAT
- Canonical SPDI
- NC_000003.12:46860701:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- functional variant Sequence Ontology [SO:0001536]
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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.
The Genome Aggregation Database (gnomAD), exomes 0.00001
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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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MYL3 | No evidence available | No evidence available |
GRCh38 GRCh37 |
372 | 385 |
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
Help
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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Apr 19, 2022 | RCV000024468.5 | |
Pathogenic (1) |
no assertion criteria provided
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Aug 1, 2015 | RCV000491596.1 | |
Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Apr 28, 2023 | RCV000824445.6 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jan 23, 2017 | RCV000769168.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 26, 2021 | RCV001290568.1 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jan 13, 2023 | RCV003162261.1 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
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The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
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 pathogenic
(Jan 23, 2017)
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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
Study: Canadian Open Genetics Repository
Accession: SCV000900543.1 First in ClinVar: May 06, 2019 Last updated: May 06, 2019 |
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Likely pathogenic
(Dec 15, 2017)
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criteria provided, single submitter
Method: clinical testing
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Hypertrophic cardiomyopathy
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000059672.6
First in ClinVar: May 03, 2013 Last updated: Aug 14, 2019 |
Comment:
The p.Arg94His variant in MYL3 has been identified in 8 individuals with HCM and segregated with disease in 10 affected relatives across these families (Fokstue … (more)
The p.Arg94His variant in MYL3 has been identified in 8 individuals with HCM and segregated with disease in 10 affected relatives across these families (Fokstue n 2008, Zou 2013, Nomura 2016, LMM data). This variant has also been identified in 1/111666 of European chromosomes and 1/33582 Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs1994747 03). Computational tools suggest that this variant does not impact the protein b ut these data are not predictive enough to rule out pathogenicity and do not out weigh the above evidence supporting pathogenicity. In summary, although addition al studies are required to fully establish its clinical significance, the p.Arg9 4His variant is likely pathogenic. ACMG/AMP Criteria applied: PP1_Strong; PM2; P S4_Moderate; BP4. (less)
Number of individuals with the variant: 13
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Pathogenic
(Jan 26, 2021)
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criteria provided, single submitter
Method: clinical testing
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Primary familial hypertrophic cardiomyopathy
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001478644.1
First in ClinVar: Feb 12, 2021 Last updated: Feb 12, 2021 |
Comment:
Variant summary: MYL3 c.281G>A (p.Arg94His) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging … (more)
Variant summary: MYL3 c.281G>A (p.Arg94His) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251298 control chromosomes. c.281G>A has been reported in the literature in multiple individuals affected with Hypertrophic Cardiomyopathy (e.g. Fokstuen_2008, Zou_2013, Walsh_2017). These data indicate that the variant is very likely to be associated with disease. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Likely pathogenic
(Apr 19, 2022)
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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: SCV000208878.12
First in ClinVar: Feb 24, 2015 Last updated: Mar 04, 2023 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; … (more)
Not observed at significant frequency in large population cohorts (gnomAD); 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: 26443374, 18409188, 23283745, 27532257, 29398688, 27535533, 34638741) (less)
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Likely pathogenic
(Jan 13, 2023)
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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: SCV003901257.1
First in ClinVar: Apr 15, 2023 Last updated: Apr 15, 2023 |
Comment:
The p.R94H variant (also known as c.281G>A), located in coding exon 3 of the MYL3 gene, results from a G to A substitution at nucleotide … (more)
The p.R94H variant (also known as c.281G>A), located in coding exon 3 of the MYL3 gene, results from a G to A substitution at nucleotide position 281. The arginine at codon 94 is replaced by histidine, an amino acid with highly similar properties. This variant has been detected in several unrelated individuals with hypertrophic cardiomyopathy (HCM) and segregated with HCM in two families in which it appeared to arise from a common ancestor (Fokstuen S et al. Hum Mutat, 2008 Jun;29:879-85; Nomura A et al. J Cardiol, 2016 Feb;67:133-9; Walsh R et al. Genet Med, 2017 02;19:192-203). This variant has also been seen in individuals with HCM who had variants in other cardiomyopathy-related genes (Zou Y et al. Mol Biol Rep, 2013 Jun;40:3969-76; Lopes LR et al. Amyloid, 2019 Dec;26:243-247). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. (less)
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Pathogenic
(Apr 28, 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: SCV000965343.3
First in ClinVar: Aug 14, 2019 Last updated: Feb 20, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. An algorithm developed to predict the effect of missense changes on protein structure and function … (more)
For these reasons, this variant has been classified as Pathogenic. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant  is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 31777). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 18409188, 23283745, 26443374, 27532257, 29398688). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs199474703, gnomAD 0.003%). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 94 of the MYL3 protein (p.Arg94His). (less)
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Pathogenic
(Aug 01, 2015)
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no assertion criteria provided
Method: research
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Hypertrophic cardiomyopathy 8
Affected status: yes
Allele origin:
germline
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Department of Cardiovascular and Internal Medicine, Kanazawa University Graduate School of Medicine
Accession: SCV000579494.1
First in ClinVar: Jun 25, 2017 Last updated: Jun 25, 2017 |
Observation 1:
Clinical Features:
Hypertrophic Cardiomyopathy (present)
Family history: yes
Segregation observed: yes
Secondary finding: no
Observation 2:
Clinical Features:
Hypertrophic Cardiomyopathy (present)
Family history: yes
Segregation observed: yes
Secondary finding: no
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not provided
(Mar 18, 2012)
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no classification provided
Method: curation
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not specified
Affected status: not provided
Allele origin:
germline
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Leiden Muscular Dystrophy (MYL3)
Accession: SCV000045771.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
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Germline Functional Evidence
Functional
Help
The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence |
Method
Help
A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter. |
Result
Help
A brief description of the result of this method for 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 functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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has functional consequence
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Leiden Muscular Dystrophy (MYL3)
Accession: SCV000045771.1
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Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Prevalence of TTR variants detected by whole-exome sequencing in hypertrophic cardiomyopathy. | Lopes LR | Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis | 2019 | PMID: 31554435 |
Late Gadolinium Enhancement for Prediction of Mutation-Positive Hypertrophic Cardiomyopathy on the Basis of Panel-Wide Sequencing. | Teramoto R | Circulation journal : official journal of the Japanese Circulation Society | 2018 | PMID: 29398688 |
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 |
Whole exome sequencing combined with integrated variant annotation prediction identifies a causative myosin essential light chain variant in hypertrophic cardiomyopathy. | Nomura A | Journal of cardiology | 2016 | PMID: 26443374 |
Multiple gene mutations, not the type of mutation, are the modifier of left ventricle hypertrophy in patients with hypertrophic cardiomyopathy. | Zou Y | Molecular biology reports | 2013 | PMID: 23283745 |
A DNA resequencing array for pathogenic mutation detection in hypertrophic cardiomyopathy. | Fokstuen S | Human mutation | 2008 | PMID: 18409188 |
Text-mined citations for rs199474703 ...
HelpRecord last updated Feb 28, 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.