rs28937597

chr5-137870821-C-T

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 14P and 1B. PS1_Moderate 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. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt.

• 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

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

Verdict is Pathogenic. Variant got 13 ACMG points.

• PS1: Transcript NM_006790.3 (MYOT) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• 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
• 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 id is 5834.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-137870821-C-T is described in Lovd as [Pathogenic]. Variant chr5-137870821-C-T is described in Lovd as [Pathogenic].
• 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/exons	MANE	UniProt
MYOT	NM_006790.3	c.170C>T	p.Thr57Ile	missense_variant	2/10	ENST00000239926.9
PKD2L2-DT	XR_948815.3	n.303-11558G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYOT	ENST00000239926.9	c.170C>T	p.Thr57Ile	missense_variant	2/10	1	NM_006790.3	P1
PKD2L2-DT	ENST00000514616.6	n.320-11558G>A		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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

Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 01, 2000	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Oct 25, 2023	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). 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 tolerated. Experimental studies have shown that this missense change affects MYOT function (PMID: 16801328). For these reasons, this variant has been classified as Pathogenic. -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 06, 2023	- -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 23, 2023	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) -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 23, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 28, 2016	- -

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
MutationTaster	Benign	0.67	A;A;A
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs28937597; hg19: chr5-137206510;