ClinVar Genomic variation as it relates to human health
NM_016599.5(MYOZ2):c.738A>G (p.Ile246Met)
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_016599.5(MYOZ2):c.738A>G (p.Ile246Met)
Variation ID: 30509 Accession: VCV000030509.21
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 4q26 4: 119186143 (GRCh38) [ NCBI UCSC ] 4: 120107298 (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 Apr 15, 2024 Nov 24, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_016599.5:c.738A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_057683.1:p.Ile246Met missense NC_000004.12:g.119186143A>G NC_000004.11:g.120107298A>G NG_029747.1:g.55360A>G LRG_396:g.55360A>G LRG_396t1:c.738A>G LRG_396p1:p.Ile246Met Q9NPC6:p.Ile246Met - Protein change
- I246M
- Other names
- -
- Canonical SPDI
- NC_000004.12:119186142:A:G
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- probably has functional consequence
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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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0.00080 (G)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00020
1000 Genomes Project 30x 0.00062
1000 Genomes Project 0.00080
Exome Aggregation Consortium (ExAC) 0.00190
The Genome Aggregation Database (gnomAD), exomes 0.00214
The Genome Aggregation Database (gnomAD) 0.00220
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 | ||
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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
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. |
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MYOZ2 | - | - |
GRCh38 GRCh37 |
240 | 266 |
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. |
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Pathogenic (1) |
no assertion criteria provided
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Jan 1, 2013 | RCV000023466.3 | |
Benign (5) |
criteria provided, multiple submitters, no conflicts
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May 1, 2022 | RCV000024477.13 | |
Likely benign (1) |
criteria provided, single submitter
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Sep 21, 2012 | RCV000039013.6 | |
Benign (1) |
criteria provided, single submitter
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Nov 24, 2023 | RCV000330572.6 |
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. |
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Benign
(Jan 04, 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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GeneDx
Accession: SCV001949050.2
First in ClinVar: Oct 02, 2021 Last updated: Mar 04, 2023 |
Comment:
This variant is associated with the following publications: (PMID: 22987565, 23299917, 17347475)
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Benign
(May 01, 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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV004148789.4
First in ClinVar: Nov 20, 2023 Last updated: Apr 15, 2024 |
Comment:
MYOZ2: BP4, BS1, BS2
Number of individuals with the variant: 1
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Likely benign
(Sep 21, 2012)
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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: SCV000062691.6
First in ClinVar: May 03, 2013 Last updated: Aug 26, 2019 |
Comment:
Ile246Met in exon 6 of MYOZ2: This variant is not expected to have clinical sign ificance because it has been identified in 2.1% (4/186) of … (more)
Ile246Met in exon 6 of MYOZ2: This variant is not expected to have clinical sign ificance because it has been identified in 2.1% (4/186) of Finnish chromosomes ( 1000 Genomes Project, dbSNP rs140126678). In addition, the affected amino acid is poorly conserved in evolution, also suggesting that a change at this position is tolerated. Ile246Met in exon 6 of MYOZ2 (rs140126678; allele frequency = 2. 1%, 4/186) (less)
Number of individuals with the variant: 2
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Benign
(Nov 24, 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: SCV001000648.5
First in ClinVar: Dec 17, 2019 Last updated: Feb 28, 2024 |
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Pathogenic
(Jan 01, 2013)
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no assertion criteria provided
Method: literature only
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CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 16
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000044757.2
First in ClinVar: Apr 04, 2013 Last updated: Jul 04, 2014 |
Comment on evidence:
In a patient with hypertrophic cardiomyopathy (CMH16; 613838), Osio et al. (2007) identified heterozygosity for an A-G transition at nucleotide position 50,278 in exon 6 … (more)
In a patient with hypertrophic cardiomyopathy (CMH16; 613838), Osio et al. (2007) identified heterozygosity for an A-G transition at nucleotide position 50,278 in exon 6 of the MYOZ2 gene, resulting in an ile246-to-met (I246M) substitution at a highly conserved residue. The patient had 2 deceased sibs with CMH. The mutation was not found in 2 unaffected offspring or in 517 unaffected controls, including 405 white individuals. Ruggiero et al. (2013) generated transgenic mice carrying the Myoz2 I246M mutation and observed the development of cardiac hypertrophy with preserved systolic function; histologic examination revealed increased cardiac myocytes and interstitial fibrosis. Immunofluorescence staining showed colocalization of wildtype and mutant Myoz2 proteins with alpha-actinin (see 102573) at the Z discs, and electron microscopy revealed disrupted and malaligned Z discs in the mutant mice. (less)
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Likely benign
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics, Academic Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001918998.1 First in ClinVar: Sep 25, 2021 Last updated: Sep 25, 2021 |
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Likely benign
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001951696.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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not provided
(Apr 20, 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 (MYOZ2)
Accession: SCV000045781.1
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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probably has functional consequence
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Leiden Muscular Dystrophy (MYOZ2)
Accession: SCV000045781.1
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Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Pathogenesis of hypertrophic cardiomyopathy caused by myozenin 2 mutations is independent of calcineurin activity. | Ruggiero A | Cardiovascular research | 2013 | PMID: 22987565 |
Myozenin 2 is a novel gene for human hypertrophic cardiomyopathy. | Osio A | Circulation research | 2007 | PMID: 17347475 |
Text-mined citations for rs140126678 ...
HelpRecord last updated Apr 15, 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.