ClinVar Genomic variation as it relates to human health
NM_000258.3(MYL3):c.445A>G (p.Met149Val)
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.445A>G (p.Met149Val)
Variation ID: 14061 Accession: VCV000014061.5
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p21.31 3: 46859511 (GRCh38) [ NCBI UCSC ] 3: 46901001 (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 28, 2024 Aug 23, 2021 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000258.3:c.445A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000249.1:p.Met149Val missense NC_000003.12:g.46859511T>C NC_000003.11:g.46901001T>C NG_007555.2:g.27659A>G LRG_395:g.27659A>G LRG_395t1:c.445A>G LRG_395p1:p.Met149Val P08590:p.Met149Val - Protein change
- M149V
- Other names
- p.M149V:ATG>GTG
- Canonical SPDI
- NC_000003.12:46859510:T:C
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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.
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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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MYL3 | No evidence available | No evidence available |
GRCh38 GRCh37 |
372 | 383 |
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 (2) |
no assertion criteria provided
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Nov 1, 2005 | RCV000015105.23 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 31, 2017 | RCV000158948.4 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 23, 2021 | RCV000168418.3 |
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
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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
(Aug 31, 2017)
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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: SCV000208883.13
First in ClinVar: Feb 24, 2015 Last updated: Dec 19, 2017 |
Comment:
The Met149Val mutation in the MYL3 gene has been published in association with HCM (Poetter K et al., 1996; Arad M et al., 2005). Poetter … (more)
The Met149Val mutation in the MYL3 gene has been published in association with HCM (Poetter K et al., 1996; Arad M et al., 2005). Poetter et al. reported Met149Val to co-segregate with HCM in one family, and did not detect the mutation in 378 control chromosomes from healthy individuals. Six of the 13 family members with HCM had a phenotype involving mid left ventricular chamber (MVC) thickening apparent in a left ventriculogram (Poetter K et al., 1996). Additionally, this study performed in vitro motility assays and demonstrated that myosin from patients with the Met149Val mutation translocated actin filaments somewhat faster than the control myosin. Arad et al. reported the Met149Val mutation in a 23 year old individual with HCM, who presented with palpitations. Previous clinical evaluations in this individual's relatives identified apical HCM in 5 individuals, and typical asymmetrical hypertrophy of the anterior basal septum in 6 individuals. Two other individuals in the family were reported to have heart failure, and 3 others had sudden death. Although Met149Val results in a conservative amino acid replacement of one non-polar residue for another, the Met149 residue is highly conserved across species. Mutations affecting nearby codons (Glu143Lys, Gly152Lys, Arg154His) have been reported in association with HCM, further supporting the functional importance of this region of the protein. In silico analysis predicts this change to be probably damaging to the structure/function of the protein. Furthermore, Met149Val was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Of note, studies performed on transgenic rabbits harboring the Met149Val mutation in the MYL3 gene failed to recapitulate an HCM phenotype (James J et al., 2002). However, the authors acknowledged the association of Met149Val with HCM in humans and noted that the conflicting data may be due to the young age of the animals used. In summary, Met149Val in the MYL3 gene is interpreted as a disease-causing mutation. The variant is found in HCM panel(s). (less)
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Pathogenic
(Aug 23, 2021)
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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: SCV000219113.5
First in ClinVar: Mar 29, 2015 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces methionine with valine at codon 149 of the MYL3 protein (p.Met149Val). The methionine residue is moderately conserved and there is a … (more)
This sequence change replaces methionine with valine at codon 149 of the MYL3 protein (p.Met149Val). The methionine residue is moderately conserved and there is a small physicochemical difference between methionine and valine. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 8673105, 16267253). It has also been observed to segregate with disease in related individuals. Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this missense change affects MYL3 function (PMID: 22131351). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Nov 01, 2005)
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no assertion criteria provided
Method: literature only
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CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 8
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000035362.2
First in ClinVar: Apr 04, 2013 Last updated: Sep 09, 2018 |
Comment on evidence:
In affected members of a large 3-generation family segregating autosomal dominant hypertrophic cardiomyopathy (CMH8; 608751), Poetter et al. (1996) identified heterozygosity for an A-G transition … (more)
In affected members of a large 3-generation family segregating autosomal dominant hypertrophic cardiomyopathy (CMH8; 608751), Poetter et al. (1996) identified heterozygosity for an A-G transition in the MYL3 gene, resulting in a met149-to-val (M149V) substitution at a highly conserved residue. Six of 13 affected family members had unusual mid-left ventricular chamber thickening on echocardiography. An in vitro motility assay of ventricular myosins from 3 mutation-positive individuals demonstrated an increased rate of actin translocation compared to controls. Soleus or deltoid muscle biopsies from the same 3 patients showed myopathic changes and a ragged-red fiber pattern characteristic of primary mitochondrial disease; cytochrome oxidase-positive subsarcolemmal accumulations were confirmed to be mitochondria by electron microscopy. The M149V mutation was not found in 378 control chromosomes or in 762 chromosomes from unrelated CMH kindreds. In the proband from a CMH family previously described by Maron et al. (1982), in which 6 of 12 affected members had typical asymmetric hypertrophy and 6 had ventricular septal hypertrophy that was localized to the apical region of the left ventricle, Arad et al. (2005) identified heterozygosity for the M149V mutation. Two members of the family had died of heart failure, at 35 and 54 years of age, respectively, and sudden death had occurred in 3 individuals, at ages 26, 33, and 35 years, respectively. (less)
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not provided
(Mar 18, 2012)
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no classification provided
Method: curation
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Familial hypertrophic cardiomyopathy 8
Affected status: not provided
Allele origin:
germline
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Leiden Muscular Dystrophy (MYL3)
Accession: SCV000045769.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
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Germline Functional Evidence
Functional
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The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence |
Method
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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
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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
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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: SCV000045769.1
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Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Mutations of ventricular essential myosin light chain disturb myosin binding and sarcomeric sorting. | Lossie J | Cardiovascular research | 2012 | PMID: 22131351 |
Gene mutations in apical hypertrophic cardiomyopathy. | Arad M | Circulation | 2005 | PMID: 16267253 |
Mutations in either the essential or regulatory light chains of myosin are associated with a rare myopathy in human heart and skeletal muscle. | Poetter K | Nature genetics | 1996 | PMID: 8673105 |
Hypertrophic cardiomyopathy with ventricular septal hypertrophy localized to the apical region of the left ventricle (apical hypertrophic cardiomyopathy). | Maron BJ | The American journal of cardiology | 1982 | PMID: 6211078 |
Text-mined citations for rs104893748 ...
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.