rs121908461

Positions:

• chr5-137870767-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PP5_Very_Strong

The ENST00000239926.9(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 (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYOT ENST00000239926.9 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 10 ACMG points.

• 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/exons	MANE	Protein	UniProt
MYOT	NM_006790.3	c.116C>T	p.Ser39Phe	missense_variant	2/10	ENST00000239926.9	NP_006781.1
PKD2L2-DT	XR_948815.3	n.303-11504G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYOT	ENST00000239926.9	c.116C>T	p.Ser39Phe	missense_variant	2/10	1	NM_006790.3	ENSP00000239926	P1
PKD2L2-DT	ENST00000514616.6	n.320-11504G>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:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Myofibrillar myopathy 3 Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 14, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 11, 2022	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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). -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 27, 2005	- -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Athena Diagnostics

May 05, 2017

- -

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
MutationTaster	Benign	1.0	A;A;A
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;