Published functional studies demonstrate reduced degradation of myotilin (PMID: 21361873, 22349301); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; This variant is associated with the following publications: (PMID: 34440373, 31561939, 22349301, 15947064, 15111675, 27618136, 21361873, 32403337, 32041727, 22021208, 26842778, 21676617)
ClinVar Genomic variation as it relates to human health
NM_006790.3(MYOT):c.179C>G (p.Ser60Cys)
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.
(10)
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.
Pathogenic
10
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_006790.3(MYOT):c.179C>G (p.Ser60Cys)
Variation ID: 5836 Accession: VCV000005836.23
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 5q31.2 5: 137870830 (GRCh38) [ NCBI UCSC ] 5: 137206519 (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 Aug 29, 2016 Sep 29, 2024 Mar 5, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_006790.3:c.179C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_006781.1:p.Ser60Cys missense NM_001135940.2:c.-197+305C>G intron variant NM_001300911.2:c.-120-47C>G intron variant NC_000005.10:g.137870830C>G NC_000005.9:g.137206519C>G NG_008894.1:g.7975C>G LRG_201:g.7975C>G LRG_201t1:c.179C>G LRG_201p1:p.Ser60Cys - Protein change
- S60C
- Other names
- -
- Canonical SPDI
- NC_000005.10:137870829:C:G
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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
Help
The frequency of the allele represented by this VCV record.
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- 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. |
|||
| MYOT | - | - |
GRCh38 GRCh37 |
2 | 434 | |
| PKD2L2-DT | - | - | - | GRCh38 | - | 419 |
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. |
|---|---|---|---|---|
| Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
|
Jan 10, 2024 | RCV000006193.28 | |
| Pathogenic (1) |
no assertion criteria provided
|
Aug 16, 2016 | RCV000239643.8 | |
| Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Mar 5, 2024 | RCV000725007.24 |
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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|---|---|---|---|---|---|
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Pathogenic
(Oct 13, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000333146.4
First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 19
Sex: mixed
|
|
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Pathogenic
(Dec 28, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Myofibrillar myopathy 3
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002017711.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
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Pathogenic
(Mar 05, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV001812081.4
First in ClinVar: Sep 08, 2021 Last updated: Sep 29, 2024 |
Comment:
Published functional studies demonstrate reduced degradation of myotilin (PMID: 21361873, 22349301); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports … (more)
Published functional studies demonstrate reduced degradation of myotilin (PMID: 21361873, 22349301); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; This variant is associated with the following publications: (PMID: 34440373, 31561939, 22349301, 15947064, 15111675, 27618136, 21361873, 32403337, 32041727, 22021208, 26842778, 21676617) (less)
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|
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Pathogenic
(Jul 08, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: unknown
Allele origin:
germline
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV001714143.1
First in ClinVar: Jun 15, 2021 Last updated: Jun 15, 2021 |
Comment:
PS3, PS4_moderate, PM2, PP4, PP5
Number of individuals with the variant: 2
|
|
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Pathogenic
(Sep 21, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Myofibrillar myopathy 3
Affected status: yes
Allele origin:
germline
|
Centogene AG - the Rare Disease Company
Accession: SCV002059614.1
First in ClinVar: Jan 14, 2022 Last updated: Jan 14, 2022 |
|
|
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Pathogenic
(Sep 07, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Athena Diagnostics
Accession: SCV002770883.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
Comment:
This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with clinical features associated … (more)
This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with clinical features associated with this gene. At least one other missense variant at this codon is considered to be pathogenic or likely pathogenic, suggesting this variant may also cause disease. Assessment of experimental evidence suggests this variant results in abnormal protein function. This variant affected protein organization in muscle cells (PMID: 22349301). (less)
|
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Pathogenic
(Sep 18, 2021)
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criteria provided, single submitter
Method: clinical testing
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Myofibrillar myopathy 3
Myofibrillar myopathy 3
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002811520.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
|
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Pathogenic
(Jan 10, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Myofibrillar myopathy 3
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000638812.8
First in ClinVar: Dec 26, 2017 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 60 of the MYOT protein … (more)
This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 60 of the MYOT protein (p.Ser60Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with myofibrillar myopathy (PMID: 15111675, 16684602, 19225410, 21676617, 22349301, 26842778). ClinVar contains an entry for this variant (Variation ID: 5836). 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 MYOT function (PMID: 21361873, 22349301). This variant disrupts the p.Ser60 amino acid residue in MYOT. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16684602, 16793270, 19590214, 26842778). 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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Pathogenic
(Apr 27, 2004)
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no assertion criteria provided
Method: literature only
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MYOPATHY, MYOFIBRILLAR, 3
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000026375.5
First in ClinVar: Apr 04, 2013 Last updated: Sep 28, 2018 |
Comment on evidence:
In 3 unrelated patients with myofibrillar myopathy (MFM3; 609200), Selcen and Engel (2004) identified a heterozygous 459C-G transversion in exon 2 of the TTID gene, … (more)
In 3 unrelated patients with myofibrillar myopathy (MFM3; 609200), Selcen and Engel (2004) identified a heterozygous 459C-G transversion in exon 2 of the TTID gene, resulting in a ser60-to-cys (S60C) substitution in the hydrophobic stretch of the protein. The patients had distal muscle weakness and peripheral neuropathy. One of the patients had cardiomyopathy and 2 had increased serum creatine kinase. The S60C mutation was not identified in 200 control chromosomes. Another unrelated patient had a different mutation in the same codon (S60F; 604103.0004). (less)
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Pathogenic
(Aug 16, 2016)
|
no assertion criteria provided
Method: clinical testing
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Myofibrillar myopathy
Affected status: yes
Allele origin:
unknown
|
Wellcome Centre for Mitochondrial Research, Newcastle University
Accession: SCV000298021.1
First in ClinVar: Aug 29, 2016 Last updated: Aug 29, 2016 |
Number of individuals with the variant: 2
|
Comment:
Comment:
PS3, PS4_moderate, PM2, PP4, PP5
Comment:
This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with clinical features associated with this gene. At least one other missense variant at this codon is considered to be pathogenic or likely pathogenic, suggesting this variant may also cause disease. Assessment of experimental evidence suggests this variant results in abnormal protein function. This variant affected protein organization in muscle cells (PMID: 22349301).
Comment:
This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 60 of the MYOT protein (p.Ser60Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with myofibrillar myopathy (PMID: 15111675, 16684602, 19225410, 21676617, 22349301, 26842778). ClinVar contains an entry for this variant (Variation ID: 5836). 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 MYOT function (PMID: 21361873, 22349301). This variant disrupts the p.Ser60 amino acid residue in MYOT. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16684602, 16793270, 19590214, 26842778). 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.
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. |
Comment:
Published functional studies demonstrate reduced degradation of myotilin (PMID: 21361873, 22349301); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; This variant is associated with the following publications: (PMID: 34440373, 31561939, 22349301, 15947064, 15111675, 27618136, 21361873, 32403337, 32041727, 22021208, 26842778, 21676617)
Comment:
PS3, PS4_moderate, PM2, PP4, PP5
Comment:
This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with clinical features associated with this gene. At least one other missense variant at this codon is considered to be pathogenic or likely pathogenic, suggesting this variant may also cause disease. Assessment of experimental evidence suggests this variant results in abnormal protein function. This variant affected protein organization in muscle cells (PMID: 22349301).
Comment:
This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 60 of the MYOT protein (p.Ser60Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with myofibrillar myopathy (PMID: 15111675, 16684602, 19225410, 21676617, 22349301, 26842778). ClinVar contains an entry for this variant (Variation ID: 5836). 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 MYOT function (PMID: 21361873, 22349301). This variant disrupts the p.Ser60 amino acid residue in MYOT. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16684602, 16793270, 19590214, 26842778). 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.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Clinical Reasoning: A case of bilateral foot drop in a 74-year-old man. | Harada Y | Neurology | 2020 | PMID: 32041727 |
| Mitochondrial dysfunction in myofibrillar myopathy. | Vincent AE | Neuromuscular disorders : NMD | 2016 | DOI: 10.1016/j.nmd.2016.08.004 |
| Mitochondrial dysfunction in myofibrillar myopathy. | Vincent AE | Neuromuscular disorders : NMD | 2016 | PMID: 27618136 |
| New insights into the protein aggregation pathology in myotilinopathy by combined proteomic and immunolocalization analyses. | Maerkens A | Acta neuropathologica communications | 2016 | PMID: 26842778 |
| In vivo characterization of mutant myotilins. | Keduka E | The American journal of pathology | 2012 | PMID: 22349301 |
| Myotilin dynamics in cardiac and skeletal muscle cells. | Wang J | Cytoskeleton (Hoboken, N.J.) | 2011 | PMID: 22021208 |
| Clinical and myopathological evaluation of early- and late-onset subtypes of myofibrillar myopathy. | Olivé M | Neuromuscular disorders : NMD | 2011 | PMID: 21676617 |
| Analysis of myotilin turnover provides mechanistic insight into the role of myotilinopathy-causing mutations. | von Nandelstadh P | The Biochemical journal | 2011 | PMID: 21361873 |
| Lower limb radiology of distal myopathy due to the S60F myotilin mutation. | McNeill A | European neurology | 2009 | PMID: 19590214 |
| TAR DNA-Binding protein 43 accumulation in protein aggregate myopathies. | Olivé M | Journal of neuropathology and experimental neurology | 2009 | PMID: 19225410 |
| Expression of mutant ubiquitin (UBB+1) and p62 in myotilinopathies and desminopathies. | Olivé M | Neuropathology and applied neurobiology | 2008 | PMID: 17931355 |
| Oxidative stress in desminopathies and myotilinopathies: a link between oxidative damage and abnormal protein aggregation. | Janué A | Brain pathology (Zurich, Switzerland) | 2007 | PMID: 17784878 |
| Myotilinopathy in a family with late onset myopathy. | Pénisson-Besnier I | Neuromuscular disorders : NMD | 2006 | PMID: 16793270 |
| Different early pathogenesis in myotilinopathy compared to primary desminopathy. | Fischer D | Neuromuscular disorders : NMD | 2006 | PMID: 16684602 |
| Myotilinopathy: refining the clinical and myopathological phenotype. | Olivé M | Brain : a journal of neurology | 2005 | PMID: 15947064 |
| Mutations in myotilin cause myofibrillar myopathy. | Selcen D | Neurology | 2004 | PMID: 15111675 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=MYOT | - | - | - | - |
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Text-mined citations for rs121908458 ...
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 Nov 19, 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.