ClinVar Genomic variation as it relates to human health
NM_000258.3(MYL3):c.517A>G (p.Met173Val)
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
-
NM_000258.3(MYL3):c.517A>G (p.Met173Val)
Variation ID: 31779 Accession: VCV000031779.20
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 3p21.31 3: 46858426 (GRCh38) [ NCBI UCSC ] 3: 46899916 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Apr 20, 2024 Jan 15, 2024 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_000258.3:c.517A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000249.1:p.Met173Val missense NC_000003.12:g.46858426T>C NC_000003.11:g.46899916T>C NG_007555.2:g.28744A>G LRG_395:g.28744A>G LRG_395t1:c.517A>G LRG_395p1:p.Met173Val - Protein change
- M173V
- Other names
- p.M173V:ATG>GTG
- Canonical SPDI
- NC_000003.12:46858425:T:C
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- functional variant Sequence Ontology [SO:0001536]
-
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.
-
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00000
Trans-Omics for Precision Medicine (TOPMed) 0.00002
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 | ||
---|---|---|---|---|---|---|
HI score
Help
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. |
|||
MYL3 | No evidence available | No evidence available |
GRCh38 GRCh37 |
- | - |
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. |
---|---|---|---|---|
Uncertain significance (2) |
criteria provided, single submitter
|
Sep 13, 2022 | RCV000024470.6 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
|
Jan 8, 2024 | RCV000036029.8 | |
Uncertain significance (1) |
criteria provided, single submitter
|
Apr 19, 2023 | RCV001189931.4 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
|
Jan 15, 2024 | RCV001857366.4 | |
Uncertain significance (1) |
criteria provided, single submitter
|
Oct 19, 2021 | RCV002482904.1 |
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. |
|
---|---|---|---|---|---|
Uncertain significance
(Oct 19, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Hypertrophic cardiomyopathy 8
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002779679.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
|
Uncertain significance
(Sep 13, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000208889.16
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 does not alter protein structure/function; This variant … (more)
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26385864, 27532257, 28301460, 18403758, 33662488, 26582918) (less)
|
|
Uncertain significance
(Jan 15, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Hypertrophic cardiomyopathy
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV002204324.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 173 of the MYL3 protein (p.Met173Val). … (more)
This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 173 of the MYL3 protein (p.Met173Val). This variant is present in population databases (rs199474708, gnomAD 0.0009%). This missense change has been observed in individual(s) with dilated cardiomyopathy and/or hypertrophic cardiomyopathy (PMID: 18403758, 27532257, 33662488). ClinVar contains an entry for this variant (Variation ID: 31779). 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 disruptive. Experimental studies have shown that this missense change affects MYL3 function (PMID: 26385864). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
|
|
Uncertain significance
(Jan 08, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV004804239.1
First in ClinVar: Mar 30, 2024 Last updated: Mar 30, 2024 |
Comment:
Variant summary: MYL3 c.517A>G (p.Met173Val) results in a conservative amino acid change located in the EF-hand domain (IPR002048) of the encoded protein sequence. Four of … (more)
Variant summary: MYL3 c.517A>G (p.Met173Val) results in a conservative amino acid change located in the EF-hand domain (IPR002048) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251116 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.517A>G has been reported in the literature in individuals affected with dilated cardiomyopathy and/or hypertrophic cardiomyopathy (examples: Morita_2008, Walsh_2017,Ho_2018, Lamounier_2022, Alimohamed_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Hypertrophic Cardiomyopathy. At least one publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (Huang_2015). The following publications have been ascertained in the context of this evaluation (PMID: 33662488, 30297972, 26385864, 33642254, 18403758, 27532257). ClinVar contains an entry for this variant (Variation ID: 31779). Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
|
|
Uncertain significance
(Sep 24, 2012)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: not provided
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000059681.6
First in ClinVar: May 03, 2013 Last updated: Apr 17, 2019 |
Comment:
Variant classified as Uncertain Significance - Favor Pathogenic. The Met173Val v ariant (MYL3) has been reported in the literature in one individual with early o … (more)
Variant classified as Uncertain Significance - Favor Pathogenic. The Met173Val v ariant (MYL3) has been reported in the literature in one individual with early o nset HCM, segregated with disease in two affected relatives (including one oblig ate carrier), and was absent from 1360 control chromosomes (Morita 2008, LMM dat a). This variant has not been identified in large and broad European American an d African American populations by the NHLBI Exome Sequencing Project (http://evs .gs.washington.edu/EVS); this low frequency is consistent with a disease causing role but insufficient to establish this with confidence. Methionine (Met) at po sition 173 is highly conserved in mammals, however computational analyses (bioch emical amino acid properties, AlignGVGD, PolyPhen2, and SIFT) do not provide str ong support for or against an impact to the normal function of the protein. Addi tional studies are needed to fully assess the clinical significance of this vari ant. (less)
Number of individuals with the variant: 4
|
|
Uncertain significance
(Apr 19, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiomyopathy
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV001357326.3
First in ClinVar: Jun 22, 2020 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces methionine with valine at codon 173 of the MYL3 protein. Computational prediction is inconclusive regarding the impact of this variant on … (more)
This missense variant replaces methionine with valine at codon 173 of the MYL3 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). An experimental functional study has shown that this variant may increase calcium sensitivity and affect function (PMID: 26385864). However, clinical significance of this finding is not clear. This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 27532257, 33495596), in an individual affected with childhood-onset cardiac hypertrophy (PMID: 18403758), and in an individual affected with dilated cardiomyopathy (PMID: 33662488). This variant has been identified in 1/251116 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
|
|
Uncertain Significance
(Jan 11, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Hypertrophic cardiomyopathy
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
All of Us Research Program, National Institutes of Health
Accession: SCV004843309.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
This missense variant replaces methionine with valine at codon 173 of the MYL3 protein. Computational prediction is inconclusive regarding the impact of this variant on … (more)
This missense variant replaces methionine with valine at codon 173 of the MYL3 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). An experimental functional study has shown that this variant may increase calcium sensitivity and affect function (PMID: 26385864). However, clinical significance of this finding is not clear. This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 27532257, 33495596), in an individual affected with childhood-onset cardiac hypertrophy (PMID: 18403758), and in an individual affected with dilated cardiomyopathy (PMID: 33662488). This variant has been identified in 1/251116 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
Number of individuals with the variant: 6
|
|
not provided
(Mar 18, 2012)
|
no classification provided
Method: curation
|
not specified
Affected status: not provided
Allele origin:
germline
|
Leiden Muscular Dystrophy (MYL3)
Accession: SCV000045773.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
|
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. |
---|---|---|---|---|
has functional consequence
|
Leiden Muscular Dystrophy (MYL3)
Accession: SCV000045773.1
|
|
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
---|---|---|---|---|
Genotype-phenotype correlations in hypertrophic cardiomyopathy: a multicenter study in Portugal and Spain of the TPM1 p.Arg21Leu variant. | Lamounier Junior A | Revista espanola de cardiologia (English ed.) | 2022 | PMID: 33642254 |
Diagnostic yield of targeted next generation sequencing in 2002 Dutch cardiomyopathy patients. | Alimohamed MZ | International journal of cardiology | 2021 | PMID: 33662488 |
Shared genetic pathways contribute to risk of hypertrophic and dilated cardiomyopathies with opposite directions of effect. | Tadros R | Nature genetics | 2021 | PMID: 33495596 |
Genotype and Lifetime Burden of Disease in Hypertrophic Cardiomyopathy: Insights from the Sarcomeric Human Cardiomyopathy Registry (SHaRe). | Ho CY | Circulation | 2018 | PMID: 30297972 |
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 |
Molecular mechanisms of cardiomyopathy phenotypes associated with myosin light chain mutations. | Huang W | Journal of muscle research and cell motility | 2015 | PMID: 26385864 |
Shared genetic causes of cardiac hypertrophy in children and adults. | Morita H | The New England journal of medicine | 2008 | PMID: 18403758 |
Text-mined citations for rs199474708 ...
HelpRecord last updated Apr 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.