NM_006790.3(MYOT):c.179C>G (p.Ser60Cys) AND Myofibrillar myopathy 3

Germline classification:: Pathogenic (5 submissions)
Last evaluated:: Jan 10, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000006193.28

Allele description [Variation Report for NM_006790.3(MYOT):c.179C>G (p.Ser60Cys)]

NM_006790.3(MYOT):c.179C>G (p.Ser60Cys)

Genes:

PKD2L2-DT:PKD2L2 divergent transcript [Gene - HGNC]
MYOT:myotilin [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

5q31.2

Genomic location:

Preferred name:

NM_006790.3(MYOT):c.179C>G (p.Ser60Cys)

HGVS:

NC_000005.10:g.137870830C>G
NG_008894.1:g.7975C>G
NM_001135940.2:c.-197+305C>G
NM_001300911.2:c.-120-47C>G
NM_006790.3:c.179C>GMANE SELECT
NP_006781.1:p.Ser60Cys
NP_006781.1:p.Ser60Cys
LRG_201t1:c.179C>G
LRG_201:g.7975C>G
LRG_201p1:p.Ser60Cys
NC_000005.9:g.137206519C>G
NM_006790.2:c.179C>G
p.Ser60Cys

Protein change:

S60C; SER60CYS

Links:

OMIM: 604103.0003; dbSNP: rs121908458

NCBI 1000 Genomes Browser:

rs121908458

Molecular consequence:

NM_001135940.2:c.-197+305C>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001300911.2:c.-120-47C>G - intron variant - [Sequence Ontology: SO:0001627]
NM_006790.3:c.179C>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Myofibrillar myopathy 3 (MFM3)
Synonyms:: Limb-girdle muscular dystrophy, type 1A; Muscular dystrophy, proximal, type 1A; Spheroid body myopathy; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0012215; MedGen: C3714934; Orphanet: 266; Orphanet: 268129; OMIM: 609200

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000026375	OMIM	no assertion criteria provided	Pathogenic (Apr 27, 2004)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000638812	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 10, 2024)	germline	clinical testing	PubMed (10) [See all records that cite these PMIDs] 15111675, 19225410, 21676617, 21361873, 22349301, 16684602, 16793270, 19590214, 26842778, 28492532
SCV002017711	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 28, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002059614	Centogene AG - the Rare Disease Company	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Sep 21, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002811520	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Sep 18, 2021)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Mutations in myotilin cause myofibrillar myopathy.

Selcen D, Engel AG.

Neurology. 2004 Apr 27;62(8):1363-71. Erratum in: Neurology. 2004 Jul 27;63(2):405.

PubMed [citation]

PMID:: 15111675

TAR DNA-Binding protein 43 accumulation in protein aggregate myopathies.

Olivé M, Janué A, Moreno D, Gámez J, Torrejón-Escribano B, Ferrer I.

J Neuropathol Exp Neurol. 2009 Mar;68(3):262-73. doi: 10.1097/NEN.0b013e3181996d8f.

PubMed [citation]

PMID:: 19225410

See all PubMed Citations (11)

Details of each submission

From OMIM, SCV000026375.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

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).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000638812.8

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (10)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Revvity Omics, Revvity, SCV002017711.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Centogene AG - the Rare Disease Company, SCV002059614.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Fulgent Genetics, Fulgent Genetics, SCV002811520.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Nov 24, 2024

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