ClinVar Genomic variation as it relates to human health
NM_000258.3(MYL3):c.466G>T (p.Val156Leu)
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.
Pathogenic(1); Likely pathogenic(2); Uncertain significance(6)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000258.3(MYL3):c.466G>T (p.Val156Leu)
Variation ID: 177841 Accession: VCV000177841.22
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p21.31 3: 46859490 (GRCh38) [ NCBI UCSC ] 3: 46900980 (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 Nov 4, 2015 Feb 28, 2024 Nov 17, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000258.3:c.466G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000249.1:p.Val156Leu missense NC_000003.12:g.46859490C>A NC_000003.11:g.46900980C>A NG_007555.2:g.27680G>T LRG_395:g.27680G>T LRG_395t1:c.466G>T LRG_395p1:p.Val156Leu - Protein change
- V156L
- Other names
- p.V156L:GTG>TTG
- Canonical SPDI
- NC_000003.12:46859489: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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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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Uncertain significance (1) |
criteria provided, single submitter
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Nov 30, 2018 | RCV000154477.9 | |
Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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Jan 12, 2018 | RCV000201472.7 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Dec 15, 2021 | RCV000766488.2 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Apr 19, 2023 | RCV000769164.8 | |
Uncertain significance (1) |
criteria provided, single submitter
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- | RCV000845401.3 | |
Pathogenic (1) |
criteria provided, single submitter
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Nov 17, 2023 | RCV001309098.3 |
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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Uncertain significance
(-)
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criteria provided, single submitter
Method: clinical testing
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Hypertrophic cardiomyopathy 8
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: SCV000256195.1 First in ClinVar: Nov 04, 2015 Last updated: Nov 04, 2015 |
Number of individuals with the variant: 1
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Uncertain significance
(Sep 08, 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: SCV000208888.11
First in ClinVar: Feb 24, 2015 Last updated: Apr 17, 2019 |
Comment:
A variant of uncertain significance has been identified in the MYL3 gene. The V156L (c.466 G>T) variant has been reported previously in association with HCM; … (more)
A variant of uncertain significance has been identified in the MYL3 gene. The V156L (c.466 G>T) variant has been reported previously in association with HCM; however, clinical data was not provided and segregation studies were not performed (Walsh et al., 2017). Additionally, while a different nucleotide substitution (c.466 G>C) that also results in the V156L missense substitution and a missense variant in the same residue (V156M) were previously reported in association with HCM (Morita et al., 2006; Wang et al., 2014), the pathogenicity of these variants has not been definitively determined. Furthermore, the V156L variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Nevertheless, the V156L (c.466 G>T) variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Finally, missense variants in nearby residues (H155D, E152K) have been reported in the Human Gene Mutation Database in association with cardiomyopathy (Stenson et al., 2014), supporting the functional importance of this region of the protein. (less)
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Uncertain significance
(Nov 30, 2018)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000204146.3
First in ClinVar: Jan 31, 2015 Last updated: Dec 19, 2017 |
Comment:
The p.Val156Leu variant in MYL3 has been identified in 1 individual with HCM (LM M data). It has also been reported by other clinical laboratories … (more)
The p.Val156Leu variant in MYL3 has been identified in 1 individual with HCM (LM M data). It has also been reported by other clinical laboratories in ClinVar (Va riation ID # 177841) and has been identified in 3/113668 European chromosomes by gnomAD (http://gnomad.broadinstitute.org). Another variant (c.466G>C) resulting in the same amino acid change has been identified in 2 individuals with HCM (Wa ng 2014, Walsh 2017). In addition, another variant at this position (p.Val156Me t) has been identified in 2 individuals with increased left ventricular wall thi ckness and 5 individuals with HCM, one of whom with infantile-onset-disease (Mo rita 2006, Berge 2014, LMM data), suggesting that changes at this position may n ot be tolerated. Computational prediction tools and conservation analysis sugges t that this variant may not impact the protein, though this information is not p redictive enough to rule out pathogenicity. In summary, the clinical significanc e of the p.Val156Leu variant is uncertain. ACMG/AMP Criteria applied: BP4, PS4_S upporting. (less)
Number of individuals with the variant: 1
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Uncertain significance
(-)
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criteria provided, single submitter
Method: clinical testing
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Primary familial hypertrophic cardiomyopathy
Affected status: yes
Allele origin:
germline
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Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute
Accession: SCV000987465.1
First in ClinVar: Sep 08, 2019 Last updated: Sep 08, 2019 |
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Uncertain significance
(Jan 12, 2018)
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criteria provided, single submitter
Method: clinical testing
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Hypertrophic cardiomyopathy 8
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV001309350.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more)
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. (less)
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Likely pathogenic
(Apr 19, 2023)
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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: SCV000900539.3 First in ClinVar: May 06, 2019 Last updated: Feb 04, 2024 |
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Likely pathogenic
(Aug 01, 2017)
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criteria provided, single submitter
Method: clinical testing
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Hypertrophic cardiomyopathy 8
Affected status: unknown
Allele origin:
germline
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Phosphorus, Inc.
Accession: SCV000679803.1
First in ClinVar: Nov 04, 2015 Last updated: Nov 04, 2015 |
Number of individuals with the variant: 1
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Uncertain significance
(Dec 15, 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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AiLife Diagnostics, AiLife Diagnostics
Accession: SCV002502423.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
Number of individuals with the variant: 3
Secondary finding: no
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Pathogenic
(Nov 17, 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: SCV001498581.3
First in ClinVar: Mar 07, 2021 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 156 of the MYL3 protein (p.Val156Leu). … (more)
This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 156 of the MYL3 protein (p.Val156Leu). This variant is present in population databases (rs199474707, gnomAD 0.002%). This missense change has been observed in individuals with clinical features of hypertrophic cardiomyopathy (PMID: 25132132, 25611685, 27532257, 31737537; Invitae). ClinVar contains an entry for this variant (Variation ID: 177841). 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. This variant disrupts the p.Val156 amino acid residue in MYL3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16754800, 23549607, 24111713, 27532257; Invitae). 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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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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Variant panorama in 1,385 index patients and sensitivity of expanded next-generation sequencing panels in arrhythmogenic disorders. | Marschall C | Cardiovascular diagnosis and therapy | 2019 | PMID: 31737537 |
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 |
Results of clinical genetic testing of 2,912 probands with hypertrophic cardiomyopathy: expanded panels offer limited additional sensitivity. | Alfares AA | Genetics in medicine : official journal of the American College of Medical Genetics | 2015 | PMID: 25611685 |
Malignant effects of multiple rare variants in sarcomere genes on the prognosis of patients with hypertrophic cardiomyopathy. | Wang J | European journal of heart failure | 2014 | PMID: 25132132 |
Genetics of hypertrophic cardiomyopathy in Norway. | Berge KE | Clinical genetics | 2014 | PMID: 24111713 |
T1 measurements identify extracellular volume expansion in hypertrophic cardiomyopathy sarcomere mutation carriers with and without left ventricular hypertrophy. | Ho CY | Circulation. Cardiovascular imaging | 2013 | PMID: 23549607 |
Single-gene mutations and increased left ventricular wall thickness in the community: the Framingham Heart Study. | Morita H | Circulation | 2006 | PMID: 16754800 |
Text-mined citations for rs199474707 ...
HelpRecord last updated Mar 05, 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.