rs121908461

Variant names:

• chr5-137870767-C-T
• rs121908461
• NM_006790.3:c.116C>T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PS1_Moderate PM1 PM2 PP5_Very_Strong

The NM_006790.3(MYOT):​c.116C>T​(p.Ser39Phe) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in UniProt.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYOT NM_006790.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 5.37

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 14 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 region_of_interest Disordered (size 45) in uniprot entity MYOTI_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_006790.3
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-137870767-C-T is Pathogenic according to our data. Variant chr5-137870767-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 5839.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-137870767-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYOT	NM_006790.3	c.116C>T	p.Ser39Phe	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.116C>T	p.Ser39Phe	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

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Myofibrillar myopathy 3 Pathogenic:3

Dec 27, 2005

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Aug 14, 2023

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 30, 2024

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 39 of the MYOT protein (p.Ser39Phe). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with MYOT-related conditions (PMID: 16380616, 22106715). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 5839). 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. For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

May 05, 2017

Athena Diagnostics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Pathogenic	26
DANN	Uncertain	1.0
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.054	D
MetaRNN	Uncertain	0.69	D
MetaSVM	Benign	-0.41	T
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-2.5	N
REVEL	Uncertain	0.36
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0090	D
Vest4		0.65
MutPred		0.28		Loss of phosphorylation at S39 (P = 0.0243);
MVP		0.91
MPC		0.73
ClinPred		0.98	D
GERP RS		5.5
gMVP		0.73

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: rs121908461; hg19: chr5-137206456;