rs121908458

Variant names:

• chr5-137870830-C-G
• rs121908458
• NM_006790.3:c.179C>G

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 16P and 4B. PS3 PM1 PM5 PP5_Very_Strong BS2

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 (★★). ClinVar reports functional evidence for this variant: "SCV000638812: Experimental studies have shown that this missense change affects MYOT function (PMID:21361873, 22349301)." and additional evidence is available in ClinVar. 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:11
• Conservation: PhyloP100: 5.43
• Publications: 38 publications found

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

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000638812: Experimental studies have shown that this missense change affects MYOT function (PMID: 21361873, 22349301).; SCV001812081: Published functional studies demonstrate reduced degradation of myotilin (PMID: 21361873, 22349301); SCV002770883: Assessment of experimental evidence suggests this variant results in abnormal protein function. This variant affected protein organization in muscle cells (PMID: 22349301).
• 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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr5-137870830-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 5837.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP5: Variant 5-137870830-C-G is Pathogenic according to our data. Variant chr5-137870830-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 5836.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAdExome4 at 13 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006790.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYOT	NM_006790.3	MANE Select	c.179C>G	p.Ser60Cys	missense	Exon 2 of 10	NP_006781.1	A0A0C4DFM5
	MYOT	NM_001300911.2		c.-120-47C>G		intron	N/A	NP_001287840.1	B4DT68
	MYOT	NM_001135940.2		c.-197+305C>G		intron	N/A	NP_001129412.1	Q9UBF9-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYOT	ENST00000239926.9	TSL:1 MANE Select	c.179C>G	p.Ser60Cys	missense	Exon 2 of 10	ENSP00000239926.4	A0A0C4DFM5
	MYOT	ENST00000968642.1		c.179C>G	p.Ser60Cys	missense	Exon 2 of 10	ENSP00000638701.1
	MYOT	ENST00000968644.1		c.179C>G	p.Ser60Cys	missense	Exon 1 of 8	ENSP00000638703.1

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

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000989 AC: 11 AN: 1112008

Other (OTH) AF: 0.0000166 AC: 1 AN: 60396

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
5	-	-	Myofibrillar myopathy 3 (5)
4	-	-	not provided (4)
1	-	-	Distal myopathy (1)
1	-	-	Myofibrillar myopathy (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		5.4
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
Mutation Taster		=15/85	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs121908458; hg19: chr5-137206519;