VCV000005837.45 - ClinVar

NM_006790.3(MYOT):c.179C>T (p.Ser60Phe)

Germline

Classification

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.

(12)

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/Likely pathogenic

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>T (p.Ser60Phe)

Variation ID: 5837 Accession: VCV000005837.45

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 5q31.2 5: 137870830 (GRCh38) [ NCBI UCSC ] 5: 137206519 (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	Sep 28, 2018	Oct 20, 2024	Feb 28, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_006790.3:c.179C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_006781.1:p.Ser60Phe	missense
NM_001135940.2:c.-197+305C>T		intron variant
NM_001300911.2:c.-120-47C>T		intron variant
NC_000005.10:g.137870830C>T
NC_000005.9:g.137206519C>T
NG_008894.1:g.7975C>T
LRG_201:g.7975C>T
LRG_201t1:c.179C>T	LRG_201p1:p.Ser60Phe

... more HGVS ... less HGVS

Protein change

S60F

Other names

Canonical SPDI

NC_000005.10:137870829:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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

Trans-Omics for Precision Medicine (TOPMed) 0.00003

Exome Aggregation Consortium (ExAC) 0.00004

The Genome Aggregation Database (gnomAD), exomes 0.00004

Links

OMIM: 604103.0004 dbSNP: rs121908458 ClinGen: CA253623 VarSome

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
Gene	OMIM	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.
Myofibrillar myopathy 3	Pathogenic (6)	criteria provided, multiple submitters, no conflicts	Feb 28, 2024	RCV000006194.33
not provided	Pathogenic/Likely pathogenic (5)	criteria provided, multiple submitters, no conflicts	Dec 27, 2023	RCV000725464.39
MYOT-related disorder	Pathogenic (1)	criteria provided, single submitter	Jul 27, 2023	RCV003415664.5

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 (Oct 06, 2016)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000337124.4 First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018	Publications: PubMed (4) PubMed: 15111675‚ 15947064‚ 18653338‚ 19590214 Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=MYOT Number of individuals with the variant: 7 Sex: mixed
Pathogenic (Jul 27, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	MYOT-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004115780.1 First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023	Comment: The MYOT c.179C>T variant is predicted to result in the amino acid substitution p.Ser60Phe. This variant has been reported in the heterozygous state in many … (more) The MYOT c.179C>T variant is predicted to result in the amino acid substitution p.Ser60Phe. This variant has been reported in the heterozygous state in many unrelated individuals with myofibrillar myopathy (Selcen et al. 2004. PubMed ID: 15111675; McNeill et al. 2009. PubMed ID: 19590214; Semmler et al. 2014. PubMed ID: 25208129; Finsterer et al. 2020 PubMed ID: 32509353; Pénisson-Besnier et al. 2006. PubMed ID: 16793270). Additionally, an alternate substitution at this amino acid position (p.Ser60Cys) has been reported as causative in individuals with myofibrillar myopathy (Selcen et al. 2004. PubMed ID: 15111675). This variant is reported in 0.0071% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/5-137206519-C-T). This variant is interpreted as pathogenic. (less)
Pathogenic (Nov 13, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Myofibrillar myopathy 3 Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV002018188.3 First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024
Pathogenic (Feb 28, 2024)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Myofibrillar myopathy 3 Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV004812988.1 First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024	Publications: PubMed (1) PubMed: 27854214 Comment: Variant summary: MYOT c.179C>T (p.Ser60Phe) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging … (more) Variant summary: MYOT c.179C>T (p.Ser60Phe) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.6e-05 in 249028 control chromosomes. c.179C>T has been reported in the literature in multiple individuals affected with dominant late-onset myofibrillar myopathy (e.g. Rudolf_2016). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 27854214). ClinVar contains an entry for this variant (Variation ID: 5837). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
Likely pathogenic (Dec 27, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics Laboratory, Skane University Hospital Lund Accession: SCV005199447.1 First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024
Pathogenic (Jun 07, 2019)	criteria provided, single submitter (Classification criteria August 2017) Method: clinical testing	Myofibrillar myopathy 3 (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München Accession: SCV001150179.1 First in ClinVar: Feb 03, 2020 Last updated: Feb 03, 2020	Sex: male Tissue: blood
Likely pathogenic (Mar 17, 2021)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001817074.1 First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021	Comment: Reported previously as a heterozygous change in an individual with onset of symptoms of myofibrillar myopathy at age 77 (Selcen et al., 2004; Functional studies … (more) Reported previously as a heterozygous change in an individual with onset of symptoms of myofibrillar myopathy at age 77 (Selcen et al., 2004; Functional studies of MYOT constructs encoding S60F failed to exhibit altered myotube dynamics; however, the authors suggested that other aspects of protein function not tested by their assay may be affected (Wang et al., 2011); Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 32528171, 31589614, 32419263, 32647524, 32509353, 32403337, 31407473, 25208129, 31517061, 19590214, 15111675, 22021208, 27854214) (less)
Pathogenic (May 17, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Myofibrillar myopathy 3 Affected status: yes Allele origin: germline	MGZ Medical Genetics Center Accession: SCV002579900.1 First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 Comment: ACMG criteria applied: PS3, PS4_MOD, PM3, PM2_SUP, PP1	Number of individuals with the variant: 3 Sex: male
Pathogenic (Jul 28, 2021)	criteria provided, single submitter (Athena Diagnostics Criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Athena Diagnostics Accession: SCV002770882.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022	Publications: PubMed (13) PubMed: 15111675‚ 15947064‚ 19590214‚ 18653338‚ 25208129‚ 17931355‚ 16793270‚ 21676617‚ 17784878‚ 27854214‚ 32419263‚ 31407473‚ 26842778 Comment: This variant is statistically more frequent in affected individuals than in the general population and/or healthy controls and is therefore consistent with pathogenicity. This variant … (more) This variant is statistically more frequent in affected individuals than in the general population and/or healthy controls and is therefore consistent with pathogenicity. This variant appears to be associated with disease in at least one family. At least one other missense variant at this codon is considered to be pathogenic or likely pathogenic, suggesting this variant may also cause disease. Computational tools predict that this variant is damaging. (less)
Pathogenic (Nov 15, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Myofibrillar myopathy 3 Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000638813.7 First in ClinVar: Dec 26, 2017 Last updated: Feb 28, 2024	Publications: PubMed (11) PubMed: 28492532‚ 15111675‚ 15947064‚ 16793270‚ 19225410‚ 19590214‚ 21676617‚ 25208129‚ 26842778‚ 27854214‚ 21361873 Comment: This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 60 of the MYOT protein (p.Ser60Phe). … (more) This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 60 of the MYOT protein (p.Ser60Phe). This variant is present in population databases (rs121908458, gnomAD 0.007%). This missense change has been observed in individuals with myofibrillar myopathy (PMID: 15111675, 15947064, 16793270, 19225410, 19590214, 21676617, 25208129, 26842778, 27854214). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 5837). 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). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Mar 01, 2021)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001248346.26 First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024	Number of individuals with the variant: 2
Pathogenic (Apr 27, 2004)	no assertion criteria provided Method: literature only	MYOPATHY, MYOFIBRILLAR, 3 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000026376.5 First in ClinVar: Apr 04, 2013 Last updated: Sep 28, 2018	Publications: PubMed (1) PubMed: 15111675 Comment on evidence: In a patient with myofibrillar myopathy (MFM3; 609200), Selcen and Engel (2004) identified a heterozygous 459C-T transition in exon 2 of the TTID gene, resulting … (more) In a patient with myofibrillar myopathy (MFM3; 609200), Selcen and Engel (2004) identified a heterozygous 459C-T transition in exon 2 of the TTID gene, resulting in a ser60-to-phe (S60F) substitution in the hydrophobic stretch of the protein. The patient had proximal muscle weakness, cardiomyopathy, and peripheral neuropathy. The mutation was not identified in 200 control chromosomes. Three other patients had a different mutation in the same codon (S60C; 604103.0003). (less)
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Comment:

The MYOT c.179C>T variant is predicted to result in the amino acid substitution p.Ser60Phe. This variant has been reported in the heterozygous state in many unrelated individuals with myofibrillar myopathy (Selcen et al. 2004. PubMed ID: 15111675; McNeill et al. 2009. PubMed ID: 19590214; Semmler et al. 2014. PubMed ID: 25208129; Finsterer et al. 2020 PubMed ID: 32509353; Pénisson-Besnier et al. 2006. PubMed ID: 16793270). Additionally, an alternate substitution at this amino acid position (p.Ser60Cys) has been reported as causative in individuals with myofibrillar myopathy (Selcen et al. 2004. PubMed ID: 15111675). This variant is reported in 0.0071% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/5-137206519-C-T). This variant is interpreted as pathogenic.

Comment:

Variant summary: MYOT c.179C>T (p.Ser60Phe) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.6e-05 in 249028 control chromosomes. c.179C>T has been reported in the literature in multiple individuals affected with dominant late-onset myofibrillar myopathy (e.g. Rudolf_2016). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 27854214). ClinVar contains an entry for this variant (Variation ID: 5837). Based on the evidence outlined above, the variant was classified as pathogenic.

Comment:

Reported previously as a heterozygous change in an individual with onset of symptoms of myofibrillar myopathy at age 77 (Selcen et al., 2004; Functional studies of MYOT constructs encoding S60F failed to exhibit altered myotube dynamics; however, the authors suggested that other aspects of protein function not tested by their assay may be affected (Wang et al., 2011); Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 32528171, 31589614, 32419263, 32647524, 32509353, 32403337, 31407473, 25208129, 31517061, 19590214, 15111675, 22021208, 27854214)

Comment:

This variant is statistically more frequent in affected individuals than in the general population and/or healthy controls and is therefore consistent with pathogenicity. This variant appears to be associated with disease in at least one family. At least one other missense variant at this codon is considered to be pathogenic or likely pathogenic, suggesting this variant may also cause disease. Computational tools predict that this variant is damaging.

Comment:

This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 60 of the MYOT protein (p.Ser60Phe). This variant is present in population databases (rs121908458, gnomAD 0.007%). This missense change has been observed in individuals with myofibrillar myopathy (PMID: 15111675, 15947064, 16793270, 19225410, 19590214, 21676617, 25208129, 26842778, 27854214). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 5837). 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). 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:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Differential diagnosis of vacuolar myopathies in the NGS era.	Mair D	Brain pathology (Zurich, Switzerland)	2020	PMID: 32419263
Genotype-guided diagnostic reassessment after exome sequencing in neuromuscular disorders: experiences with a two-step approach.	Krenn M	European journal of neurology	2020	PMID: 31407473
Homozygosity of the Dominant Myotilin c.179C>T (p.Ser60Phe) Mutation Causes a More Severe and Proximal Muscular Dystrophy.	Rudolf G	Journal of neuromuscular diseases	2016	PMID: 27854214
New insights into the protein aggregation pathology in myotilinopathy by combined proteomic and immunolocalization analyses.	Maerkens A	Acta neuropathologica communications	2016	PMID: 26842778
Unusual multisystemic involvement and a novel BAG3 mutation revealed by NGS screening in a large cohort of myofibrillar myopathies.	Semmler AL	Orphanet journal of rare diseases	2014	PMID: 25208129
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
Electron microscopy in myofibrillar myopathies reveals clues to the mutated gene.	Claeys KG	Neuromuscular disorders : NMD	2008	PMID: 18653338
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
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 ...

These 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 03, 2024

ClinVar Genomic variation as it relates to human health

NM_006790.3(MYOT):c.179C>T (p.Ser60Phe)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs121908458 ...