NM_006790.3:c.170C>T

Variant names:

• chr5-137870821-C-T
• rs28937597
• NM_006790.3:c.170C>T

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 12P and 1B. PM1 PM2 PP5_Very_Strong BP4

The NM_006790.3(MYOT):​c.170C>T​(p.Thr57Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYOT NM_006790.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6 O:1
• Conservation: PhyloP100: 2.77
• Publications: 19 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: Pathogenic. The variant received 11 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 10 uncertain in NM_006790.3
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-137870821-C-T is Pathogenic according to our data. Variant chr5-137870821-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 5834.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.20068157). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYOT	NM_006790.3	c.170C>T	p.Thr57Ile	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.170C>T	p.Thr57Ile	missense_variant	Exon 2 of 10	1	NM_006790.3	ENSP00000239926.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000258 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Myofibrillar myopathy 3 Pathogenic:3 Other:1

Mar 06, 2023

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 01, 2000

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jan 24, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 57 of the MYOT protein (p.Thr57Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with limb-girdle muscular dystrophy 1A in a large kindred (PMID: 3275904, 10958653). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 5834). 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 expected to disrupt MYOT protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects MYOT function (PMID: 16801328). For these reasons, this variant has been classified as Pathogenic. -

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GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

not provided Pathogenic:3

Jan 23, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported in a family with MYOT-related myopathy in published literature (Hauser et al., 2000); A mouse model carrying the equivalent variant in murine MYOT had progressive myofibrillar pathology including Z-disc streaming, excess myofibrillar vacuolization, and plaque-like myofibrillar aggregation (Garvey et al., 2006); In silico analysis supports that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are often considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 21361873, 3275904, 30907627, 32721234, 10958653, 16801328) -

Jul 28, 2016

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 31, 2024

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has not been reported in large, multi-ethnic general populations. (http://gnomad.broadinstitute.org) This variant appears to be associated with myofibrillar myopathy (LGMD1A) in at least one family, however, the available information does not rule out an apparent association due to chance. Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 16801328, 21361873) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	22
DANN	Uncertain	1.0
Eigen	Benign	-0.040
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-0.84	T
PhyloP100		2.8
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.23
Sift	Uncertain	0.0090	D
Sift4G	Benign	0.29	T
Vest4		0.24
MutPred		0.15		Loss of glycosylation at T57 (P = 0.0406);
MVP		0.81
MPC		0.29
ClinPred		0.61	D
GERP RS		6.0
gMVP		0.55
Mutation Taster		=25/75	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: rs28937597; hg19: chr5-137206510;