chr5-137870830-C-T

Variant names:

• chr5-137870830-C-T
• rs121908458
• NM_006790.3:c.179C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 12P and 4B. PM1 PM5 PP5_Very_Strong BS2

The NM_006790.3(MYOT):​c.179C>T​(p.Ser60Phe) variant causes a missense change. The variant allele was found at a frequency of 0.0000155 in 1,614,066 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S60C) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: MYOT NM_006790.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12
• Conservation: PhyloP100: 5.43
• Publications: 38 publications found

Genes affected

MYOT (HGNC:12399): (myotilin) This gene encodes a cystoskeletal protein which plays a significant role in the stability of thin filaments during muscle contraction. This protein binds F-actin, crosslinks actin filaments, and prevents latrunculin A-induced filament disassembly. Mutations in this gene have been associated with limb-girdle muscular dystrophy and myofibrillar myopathies. Several alternatively spliced transcript variants of this gene have been described, but the full-length nature of some of these variants has not been determined.[provided by RefSeq, Oct 2008]

PKD2L2-DT (HGNC:55557): (PKD2L2 divergent transcript)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_006790.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr5-137870830-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 5836.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP5: Variant 5-137870830-C-T is Pathogenic according to our data. Variant chr5-137870830-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 5837.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAdExome4 at 23 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYOT	NM_006790.3	c.179C>T	p.Ser60Phe	missense_variant	Exon 2 of 10	ENST00000239926.9	NP_006781.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYOT	ENST00000239926.9	c.179C>T	p.Ser60Phe	missense_variant	Exon 2 of 10	1	NM_006790.3	ENSP00000239926.4

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152176 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000361 AC: 9 AN: 249028 AF XY: 0.0000371

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000719

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000157 AC: 23 AN: 1461890 Hom.: 0 Cov.: 31 AF XY: 0.0000179 AC XY: 13 AN XY: 727248

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000189 AC: 21 AN: 1112008

Other (OTH) AF: 0.0000166 AC: 1 AN: 60396

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152176 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74336

African (AFR) AF: 0.00 AC: 0 AN: 41456

American (AMR) AF: 0.00 AC: 0 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000800 Hom.: 0

Bravo AF: 0.0000264

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000412 AC: 5

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Myofibrillar myopathy 3 Pathogenic:6

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt MYOT protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects MYOT function (PMID: 21361873). For these reasons, this variant has been classified as Pathogenic. -

Feb 28, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

May 17, 2022

MGZ Medical Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 07, 2019

Institute of Human Genetics Munich, TUM University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 27, 2004

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Nov 13, 2023

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:5

Mar 01, 2021

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 27, 2025

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported previously as a heterozygous change in an individual with onset of symptoms of myofibrillar myopathy at age 77 (PMID: 15111675); Reported previously in a patient with proximal weakness and atrophy in lower limbs, mild dysphagia, diminished reflexes, elevated CK levels, and abnormal NCS/EMG (PMID: 38127101); 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 (PMID: 22021208); In silico analysis suggests 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: 31517061, 25208129, 31407473, 32403337, 32509353, 32647524, 19590214, 32419263, 31589614, 39102614, 32528171, 37705100, 40413523, 37287054, 39544699, 35239206, 38127101, 22021208, 15111675, 27854214) -

Jul 28, 2021

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Dec 27, 2023

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 06, 2016

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

MYOT-related disorder Pathogenic:1

Jul 27, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Pathogenic	0.22
CADD	Pathogenic	26
DANN	Uncertain	1.0
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.051	D
MetaRNN	Uncertain	0.70	D
MetaSVM	Benign	-0.62	T
PhyloP100		5.4
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.93	N
REVEL	Uncertain	0.41
Sift	Uncertain	0.0020	D
Sift4G	Benign	0.067	T
Vest4		0.87
MVP		0.90
MPC		0.71
ClinPred		0.30	T
GERP RS		6.0
gMVP		0.71
Mutation Taster		=10/90	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs121908458; hg19: chr5-137206519;