This variant deletes 2 nucleotides in exon 7 of the MYL2 gene, creating a frameshift and premature translation stop signal in the last coding exon. This mutant transcript is predicted to escape nonsense-mediated decay and be expressed as a truncated protein. A functional study using patient-derived mRNA showed a slight reduction in active mRNA compared to wild-type controls (PMID: 32453731). This variant has been reported in homozygous state in an individual affected with infantile-onset hypertrophic cardiomyopathy; both heterozygous parents were clinically unaffected (PMID: 32453731). It has also been reported in an individual affected with non-compaction cardiomyopathy (PMID: 33731536) and in an individual affected with left ventricular non-compaction (PMID: 28855170). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Clinical relevance of loss-of-function MYL2 truncation variants in autosomal dominant cardiovascular disorders is not clearly established. 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.
ClinVar Genomic variation as it relates to human health
NM_000432.4(MYL2):c.431_432del (p.Pro144fs)
Germline
Classification
Help
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.
(7)
Help
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.
Conflicting classifications of pathogenicity
Pathogenic(1); Likely pathogenic(1); Uncertain significance(3)
Pathogenic(1); Likely pathogenic(1); Uncertain significance(3)
7
criteria provided, conflicting classifications
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000432.4(MYL2):c.431_432del (p.Pro144fs)
Variation ID: 626790 Accession: VCV000626790.16
- Type and length
-
Deletion, 2 bp
- Location
-
Cytogenetic: 12q24.11 12: 110911146-110911147 (GRCh38) [ NCBI UCSC ] 12: 111348950-111348951 (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 May 6, 2019 May 1, 2024 Aug 28, 2023 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000432.4:c.431_432del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000423.2:p.Pro144fs frameshift NM_000432.3:c.431_432delCT NC_000012.12:g.110911146_110911147del NC_000012.11:g.111348950_111348951del NG_007554.1:g.14431_14432del LRG_393:g.14431_14432del LRG_393t1:c.431_432del LRG_393p1:p.Pro144fs - Protein change
- P144fs
- Other names
- -
- Canonical SPDI
- NC_000012.12:110911145:AG:
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
loss_of_function_variant; Sequence Ontology [ SO:0002054]decreased_translational_product_level; Sequence Ontology [ SO:0001555]effect on protein degradation; Variation Ontology [ VariO:0051]
-
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.
- -
- Links
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. |
|||
| MYL2 | - | - |
GRCh38 GRCh37 |
435 | 570 | |
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. |
|---|---|---|---|---|
| Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
|
Apr 27, 2023 | RCV000770390.10 | |
| Pathogenic (1) |
no assertion criteria provided
|
Mar 17, 2020 | RCV001089865.1 | |
| Pathogenic (1) |
no assertion criteria provided
|
Aug 6, 2021 | RCV001553794.2 | |
| Pathogenic (1) |
criteria provided, single submitter
|
May 27, 2021 | RCV001507317.1 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Feb 3, 2023 | RCV003166034.2 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Aug 28, 2023 | RCV003999941.2 |
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
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. |
|
|---|---|---|---|---|---|
|
Pathogenic
(May 27, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Congenital myopathy with fiber type disproportion
Affected status: yes
Allele origin:
inherited
|
Department of Pediatrics, The University of Tokyo
Accession: SCV001712278.1
First in ClinVar: Jun 15, 2021 Last updated: Jun 15, 2021 |
Family history: yes
Segregation observed: yes
Secondary finding: no
|
|
|
Likely pathogenic
(Nov 24, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiomyopathy
Affected status: unknown
Allele origin:
germline
|
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Accession: SCV000901831.3
First in ClinVar: May 06, 2019 Last updated: Dec 29, 2021 |
|
|
|
Uncertain significance
(Apr 27, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiomyopathy
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV001358331.3
First in ClinVar: Jun 22, 2020 Last updated: Feb 14, 2024 |
Comment:
This variant deletes 2 nucleotides in exon 7 of the MYL2 gene, creating a frameshift and premature translation stop signal in the last coding exon. … (more)
This variant deletes 2 nucleotides in exon 7 of the MYL2 gene, creating a frameshift and premature translation stop signal in the last coding exon. This mutant transcript is predicted to escape nonsense-mediated decay and be expressed as a truncated protein. A functional study using patient-derived mRNA showed a slight reduction in active mRNA compared to wild-type controls (PMID: 32453731). This variant has been reported in homozygous state in an individual affected with infantile-onset hypertrophic cardiomyopathy; both heterozygous parents were clinically unaffected (PMID: 32453731). It has also been reported in an individual affected with non-compaction cardiomyopathy (PMID: 33731536) and in an individual affected with left ventricular non-compaction (PMID: 28855170). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Clinical relevance of loss-of-function MYL2 truncation variants in autosomal dominant cardiovascular disorders is not clearly established. 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
(Aug 28, 2023)
|
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: SCV004845819.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024
Comment:
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more)
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)
|
Comment:
This variant deletes 2 nucleotides in exon 7 of the MYL2 gene, creating a frameshift and premature translation stop signal in the last coding exon. … (more)
This variant deletes 2 nucleotides in exon 7 of the MYL2 gene, creating a frameshift and premature translation stop signal in the last coding exon. This mutant transcript is predicted to escape nonsense-mediated decay and be expressed as a truncated protein. A functional study using patient-derived mRNA showed a slight reduction in active mRNA compared to wild-type controls (PMID: 32453731). This variant has been reported in homozygous state in an individual affected with infantile-onset hypertrophic cardiomyopathy; both heterozygous parents were clinically unaffected (PMID: 32453731). It has also been reported in an individual affected with non-compaction cardiomyopathy (PMID: 33731536) and in an individual affected with left ventricular non-compaction (PMID: 28855170). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Clinical relevance of loss-of-function MYL2 truncation variants in autosomal dominant cardiovascular disorders is not clearly established. 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: 2
|
|
|
Uncertain significance
(Feb 03, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV003864501.2
First in ClinVar: Apr 15, 2023 Last updated: May 01, 2024 |
Comment:
The c.431_432delCT variant, located in coding exon 7 of the MYL2 gene, results from a deletion of two nucleotides at nucleotide positions 431 to 432, … (more)
The c.431_432delCT variant, located in coding exon 7 of the MYL2 gene, results from a deletion of two nucleotides at nucleotide positions 431 to 432, causing a translational frameshift with a predicted alternate stop codon (p.P144Rfs*57). This alteration occurs at the 3' terminus of theMYL2 gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 13% of the protein. However, premature stop codons are typically deleterious in nature and a significant portion of the protein is affected (Ambry internal data). This alteration has been reported as homozygous in a case report with ventricular hypertrophy and hypotonia, passing away from refractory cardiogenic shock (Manivannan SN et al. PLoS Genet, 2020 May;16:e1008639). Additionally, this alteration was found in trans with an additional alteration in MYL2 in two siblings with muscle weakness and dilated cardiomyopathy (Tamamitsu AM et al. Int Heart J, 2021 Mar;62:445-447). Lastly, this alteration was detected in a left ventricular non-compaction (LVNC) cohort; however, clinical details were limited (Wang C et al. J Am Heart Assoc, 2017 Aug;6:[ePub ahead of print]; Hirono K et al. Circ Genom Precis Med, 2020 Aug;13:e002940). Although biallelic loss of function alterations in MYL2 have been associated with autosomal recessive MYL2-related myofibrillar myopathy with cardiomyopathy, haploinsufficiency for MYL2 has not been clearly established as a mechanism of disease for autosomal dominant MYL2-related cardiomyopathy. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
|
|
|
Pathogenic
(Mar 17, 2020)
|
no assertion criteria provided
Method: research
|
Hypertrophic cardiomyopathy 10
Affected status: yes, no
Allele origin:
inherited,
unknown
|
Garg Lab, Nationwide Children's Hospital
Accession: SCV001245294.1
First in ClinVar: May 04, 2020 Last updated: May 04, 2020 |
Comment:
The variant is observed to be pathogenic only if homozygous, at least for the infantile presentation, and not pathogenic (or weakly expressed with no obvious … (more)
The variant is observed to be pathogenic only if homozygous, at least for the infantile presentation, and not pathogenic (or weakly expressed with no obvious disease) if heterozygous (less)
Observation 1:
Number of individuals with the variant: 1
Age: 0-9 years
Sex: male
Geographic origin: Tunisia
Observation 2:
Number of individuals with the variant: 1
Age: 30-39 years
Sex: male
Geographic origin: Tunisia
Observation 3:
Number of individuals with the variant: 1
Age: 20-29 years
Sex: female
Geographic origin: Tunisia
|
|
|
Pathogenic
(Aug 06, 2021)
|
no assertion criteria provided
Method: literature only
|
MYOPATHY, MYOFIBRILLAR, 12, INFANTILE-ONSET, WITH CARDIOMYOPATHY
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV001774791.1
First in ClinVar: Aug 13, 2021 Last updated: Aug 13, 2021 |
Comment on evidence:
In a male infant, born of consanguineous parents, with infantile-onset myofibrillar myopathy-12 with cardiomyopathy (MFM12; 619424), Manivannan et al. (2020) identified a homozygous 2-bp deletion … (more)
In a male infant, born of consanguineous parents, with infantile-onset myofibrillar myopathy-12 with cardiomyopathy (MFM12; 619424), Manivannan et al. (2020) identified a homozygous 2-bp deletion (c.431_432delCT, NM_000432.3) in exon 6 of the MYL2 gene, predicted to result in a frameshift and termination (Pro144ArgfsTer57) with extension of the reading frame into the 3-prime UTR, leading to the addition of 36 amino acids to the C terminus. The mutation was predicted to disrupt the EF-hand domains in the C terminus. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family and was not present in the gnomAD database. The carrier parents were clinically unaffected. Cardiac muscle tissue from the proband showed decreased protein levels of MYL2 compared to controls, although mRNA levels were similar. In vitro cellular studies showed that the mutant MYL2 variant was degraded by the proteasomal machinery, suggesting instability of the mutant protein. Expression of the mutation failed to rescue developmental lethality and cardiac muscle defects in Myl2-null Drosophila, consistent with a loss-of-function effect. Family history revealed 3 additional sibs of the proband with a similar disorder resulting in death in infancy due to cardiac failure. (less)
|
Comment:
Comment:
This variant deletes 2 nucleotides in exon 7 of the MYL2 gene, creating a frameshift and premature translation stop signal in the last coding exon. This mutant transcript is predicted to escape nonsense-mediated decay and be expressed as a truncated protein. A functional study using patient-derived mRNA showed a slight reduction in active mRNA compared to wild-type controls (PMID: 32453731). This variant has been reported in homozygous state in an individual affected with infantile-onset hypertrophic cardiomyopathy; both heterozygous parents were clinically unaffected (PMID: 32453731). It has also been reported in an individual affected with non-compaction cardiomyopathy (PMID: 33731536) and in an individual affected with left ventricular non-compaction (PMID: 28855170). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Clinical relevance of loss-of-function MYL2 truncation variants in autosomal dominant cardiovascular disorders is not clearly established. 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.
Comment:
The c.431_432delCT variant, located in coding exon 7 of the MYL2 gene, results from a deletion of two nucleotides at nucleotide positions 431 to 432, causing a translational frameshift with a predicted alternate stop codon (p.P144Rfs*57). This alteration occurs at the 3' terminus of theMYL2 gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 13% of the protein. However, premature stop codons are typically deleterious in nature and a significant portion of the protein is affected (Ambry internal data). This alteration has been reported as homozygous in a case report with ventricular hypertrophy and hypotonia, passing away from refractory cardiogenic shock (Manivannan SN et al. PLoS Genet, 2020 May;16:e1008639). Additionally, this alteration was found in trans with an additional alteration in MYL2 in two siblings with muscle weakness and dilated cardiomyopathy (Tamamitsu AM et al. Int Heart J, 2021 Mar;62:445-447). Lastly, this alteration was detected in a left ventricular non-compaction (LVNC) cohort; however, clinical details were limited (Wang C et al. J Am Heart Assoc, 2017 Aug;6:[ePub ahead of print]; Hirono K et al. Circ Genom Precis Med, 2020 Aug;13:e002940). Although biallelic loss of function alterations in MYL2 have been associated with autosomal recessive MYL2-related myofibrillar myopathy with cardiomyopathy, haploinsufficiency for MYL2 has not been clearly established as a mechanism of disease for autosomal dominant MYL2-related cardiomyopathy. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Comment:
The variant is observed to be pathogenic only if homozygous, at least for the infantile presentation, and not pathogenic (or weakly expressed with no obvious disease) if heterozygous
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. |
|---|---|---|---|---|
|
loss_of_function_variant
decreased_translational_product_level
effect on protein degradation
|
|
|
Garg Lab, Nationwide Children's Hospital
Accession: SCV001245294.1
|
|
Comment:
This variant deletes 2 nucleotides in exon 7 of the MYL2 gene, creating a frameshift and premature translation stop signal in the last coding exon. This mutant transcript is predicted to escape nonsense-mediated decay and be expressed as a truncated protein. A functional study using patient-derived mRNA showed a slight reduction in active mRNA compared to wild-type controls (PMID: 32453731). This variant has been reported in homozygous state in an individual affected with infantile-onset hypertrophic cardiomyopathy; both heterozygous parents were clinically unaffected (PMID: 32453731). It has also been reported in an individual affected with non-compaction cardiomyopathy (PMID: 33731536) and in an individual affected with left ventricular non-compaction (PMID: 28855170). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Clinical relevance of loss-of-function MYL2 truncation variants in autosomal dominant cardiovascular disorders is not clearly established. 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.
Comment:
This variant deletes 2 nucleotides in exon 7 of the MYL2 gene, creating a frameshift and premature translation stop signal in the last coding exon. This mutant transcript is predicted to escape nonsense-mediated decay and be expressed as a truncated protein. A functional study using patient-derived mRNA showed a slight reduction in active mRNA compared to wild-type controls (PMID: 32453731). This variant has been reported in homozygous state in an individual affected with infantile-onset hypertrophic cardiomyopathy; both heterozygous parents were clinically unaffected (PMID: 32453731). It has also been reported in an individual affected with non-compaction cardiomyopathy (PMID: 33731536) and in an individual affected with left ventricular non-compaction (PMID: 28855170). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Clinical relevance of loss-of-function MYL2 truncation variants in autosomal dominant cardiovascular disorders is not clearly established. 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.
Comment:
The c.431_432delCT variant, located in coding exon 7 of the MYL2 gene, results from a deletion of two nucleotides at nucleotide positions 431 to 432, causing a translational frameshift with a predicted alternate stop codon (p.P144Rfs*57). This alteration occurs at the 3' terminus of theMYL2 gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 13% of the protein. However, premature stop codons are typically deleterious in nature and a significant portion of the protein is affected (Ambry internal data). This alteration has been reported as homozygous in a case report with ventricular hypertrophy and hypotonia, passing away from refractory cardiogenic shock (Manivannan SN et al. PLoS Genet, 2020 May;16:e1008639). Additionally, this alteration was found in trans with an additional alteration in MYL2 in two siblings with muscle weakness and dilated cardiomyopathy (Tamamitsu AM et al. Int Heart J, 2021 Mar;62:445-447). Lastly, this alteration was detected in a left ventricular non-compaction (LVNC) cohort; however, clinical details were limited (Wang C et al. J Am Heart Assoc, 2017 Aug;6:[ePub ahead of print]; Hirono K et al. Circ Genom Precis Med, 2020 Aug;13:e002940). Although biallelic loss of function alterations in MYL2 have been associated with autosomal recessive MYL2-related myofibrillar myopathy with cardiomyopathy, haploinsufficiency for MYL2 has not been clearly established as a mechanism of disease for autosomal dominant MYL2-related cardiomyopathy. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Comment:
The variant is observed to be pathogenic only if homozygous, at least for the infantile presentation, and not pathogenic (or weakly expressed with no obvious disease) if heterozygous
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Poor Myocardial Compaction in a Patient with Recessive MYL2 Myopathy. | Tamamitsu AM | International heart journal | 2021 | PMID: 33731536 |
| Increased Burden of Ion Channel Gene Variants Is Related to Distinct Phenotypes in Pediatric Patients With Left Ventricular Noncompaction. | Hirono K | Circulation. Genomic and precision medicine | 2020 | PMID: 32600061 |
| Novel frameshift variant in MYL2 reveals molecular differences between dominant and recessive forms of hypertrophic cardiomyopathy. | Manivannan SN | PLoS genetics | 2020 | PMID: 32453731 |
| A Wide and Specific Spectrum of Genetic Variants and Genotype-Phenotype Correlations Revealed by Next-Generation Sequencing in Patients with Left Ventricular Noncompaction. | Wang C | Journal of the American Heart Association | 2017 | PMID: 28855170 |
Text-mined citations for rs1566147422 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated May 08, 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.