rs121908457

chr5-137870815-C-T

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 16P and 1B. PS1_Moderate PM1 PM2 PM5 PP5_Very_Strong BP4

The NM_006790.3(MYOT):c.164C>T(p.Ser55Phe) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S55P) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYOT NM_006790.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• 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 15 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, 8 uncertain in NM_006790.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr5-137870814-T-C is described in Lovd as [Pathogenic].
• PP5: Variant 5-137870815-C-T is Pathogenic according to our data. Variant chr5-137870815-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 5835.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-137870815-C-T is described in Lovd as [Pathogenic]. Variant chr5-137870815-C-T is described in Lovd as [Likely_pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.40440857).. Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYOT	NM_006790.3	c.164C>T	p.Ser55Phe	missense_variant	2/10	ENST00000239926.9
PKD2L2-DT	XR_948815.3	n.303-11552G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYOT	ENST00000239926.9	c.164C>T	p.Ser55Phe	missense_variant	2/10	1	NM_006790.3	P1
PKD2L2-DT	ENST00000514616.6	n.320-11552G>A		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Myofibrillar myopathy 3 Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Sep 02, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 11, 2022	For these reasons, this variant has been classified as Pathogenic. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on MYOT function (PMID: 21361873). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MYOT protein function. ClinVar contains an entry for this variant (Variation ID: 5835). This missense change has been observed in individuals with myofibrillar myopathy, limb-girdle muscular dystrophy, and other forms of myotilinopathies (PMID: 9027924, 12428213, 15111675, 15947064, 16684602, 21676617, 25208129, 26342832). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 55 of the MYOT protein (p.Ser55Phe). -
Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 27, 2004	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -

Progressive proximal muscle weakness;C1836609:Progressive distal muscle weakness Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Mar 19, 2014

- -

Lower limb pain;C1836450:Distal lower limb muscle weakness;C1843663:Urinary bladder sphincter dysfunction;C1848736:Distal amyotrophy;C1866141:Foot dorsiflexor weakness;C4021082:Fatty replacement of skeletal muscle;C4021726:EMG: myopathic abnormalities;C4022159:Muscle fiber inclusion bodies Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jan 01, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.20
Cadd	Uncertain	25
Dann	Uncertain	1.0
Eigen	Uncertain	0.61
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.061	D
MetaRNN	Benign	0.40	T
MetaSVM	Benign	-0.35	T
MutationTaster	Benign	0.99	A;A;A
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.4	N
REVEL	Uncertain	0.31
Sift	Uncertain	0.0010	D
Sift4G	Benign	0.18	T
Vest4		0.49
MutPred		0.24		Loss of phosphorylation at S55 (P = 0.0523);
MVP		0.92
MPC		0.43
ClinPred		0.95	D
GERP RS		6.0
gMVP		0.62

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: rs121908457; hg19: chr5-137206504; COSMIC: COSV53514808;