rs121908458

Positions:

• chr5-137870830-C-G
• chr5-137870830-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PS1_Moderate PM5 PP5_Very_Strong

The NM_006790.3(MYOT):​c.179C>G​(p.Ser60Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000889 in 1,461,890 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S60F) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: MYOT NM_006790.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 5.43

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 12 ACMG points.

• PS1: Transcript NM_006790.3 (MYOT) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• PP5: Variant 5-137870830-C-G is Pathogenic according to our data. Variant chr5-137870830-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 5836.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-137870830-C-G is described in Lovd as [Pathogenic]. Variant chr5-137870830-C-G is described in Lovd as [Pathogenic]. Variant chr5-137870830-C-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYOT	NM_006790.3	c.179C>G	p.Ser60Cys	missense_variant	2/10	ENST00000239926.9	NP_006781.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYOT	ENST00000239926.9	c.179C>G	p.Ser60Cys	missense_variant	2/10	1	NM_006790.3	ENSP00000239926.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000889 AC: 13 AN: 1461890 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 727248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.00000989

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Myofibrillar myopathy 3 Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 28, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Sep 18, 2021	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 27, 2004	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 23, 2024	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). 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 80%. 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Centogene AG - the Rare Disease Company	Sep 21, 2020	- -

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jul 08, 2020	PS3, PS4_moderate, PM2, PP4, PP5 -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 07, 2017	This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with clinical features associated with this gene. At least one other missense variant at this codon is considered to be pathogenic or likely pathogenic, suggesting this variant may also cause disease. Assessment of experimental evidence suggests this variant results in abnormal protein function. This variant affected protein organization in muscle cells (PMID: 22349301). -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 13, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 15, 2024	Published functional studies demonstrate reduced degradation of myotilin (PMID: 21361873, 22349301); Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 34440373, 31561939, 22349301, 15947064, 15111675, 27618136, 21361873, 32403337, 32041727, 22021208, 26842778, 21676617) -

Myofibrillar myopathy Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Wellcome Centre for Mitochondrial Research, Newcastle University

Aug 16, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	26
DANN	Uncertain	0.99
Eigen	Uncertain	0.64
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.054	D
MetaRNN	Uncertain	0.60	D
MetaSVM	Benign	-0.31	T
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.37
Sift	Uncertain	0.0040	D
Sift4G	Benign	0.061	T
Vest4		0.60
MutPred		0.38		Loss of glycosylation at S60 (P = 0.0182);
MVP		0.95
MPC		0.67
ClinPred		0.89	D
GERP RS		6.0
gMVP		0.70

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: rs121908458; hg19: chr5-137206519;