rs267606612

Positions:

• chrM-9479-TTTTTTCTTCGCAGGA-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PM4 PP5_Very_Strong

The ENST00000362079.2(MT-CO3):​c.281_295del​(p.Phe94_Phe98del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. Variant has been reported in ClinVar as Likely pathogenic (★★★).

• Frequency: Mitomap GenBank: Absent
• Consequence: MT-CO3 ENST00000362079.2 inframe_deletion
• Clinical Significance: Likely pathogenic reviewed by expert panel P:3 Myoglobinuria
• Conservation: PhyloP100: 7.73

Genes affected

COX3 (HGNC:):

MT-CO3 (HGNC:7422): (mitochondrially encoded cytochrome c oxidase III) Predicted to enable electron transfer activity and oxidoreduction-driven active transmembrane transporter activity. Involved in respiratory chain complex IV assembly. Part of respiratory chain complex IV. Implicated in MELAS syndrome. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PM2: No frequency data in Mitomap. Probably very rare.
• PM4: Nonframeshift variant in NON repetitive region in ENST00000362079.2.
• PP5: Variant M-9479-TTTTTTCTTCGCAGGA-T is Pathogenic according to our data. Variant chrM-9479-TTTTTTCTTCGCAGGA-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 9654.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COX3	COX3.1	c.281_295del	p.Phe94_Phe98del	inframe_deletion	1/1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MT-CO3	ENST00000362079.2	c.281_295del	p.Phe94_Phe98del	inframe_deletion	1/1			P1

Frequencies

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

We have no GnomAD4 genomes data on this position. Probably position not covered by the project.

Mitomap

Myoglobinuria

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: reviewed by expert panel

Submissions by phenotype

Mitochondrial disease Pathogenic:1

Likely pathogenic, reviewed by expert panel

curation

ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen

Feb 26, 2024

The m.9487_9501del (p.Phe94Ter) variant in MT-CO3 has been reported in one individual to date, in a teenager with myopathy and recurrent myoglobinuria (PMID: 8630495). Her muscle biopsy showed type 1 fiber predominance, many ragged red fibers (RRF) that stained heaving for SDH and were COX-negative, and 64% COX-negative fibers. Electron microscopy showed scattered areas of increased numbers of mitochondria, some of which were enlarged and irregular with disordered cristae. Complex IV activity was 14% of controls. Heteroplasmy levels were reported as 92% in muscle, 0.7% leukocytes, 0.5% in lymphocytes, and undetectable in fibroblasts. As this is the only case reported to date, PS4 could not be applied. The variant was not detected in her healthy mother’s leukocytes. However, this expert panel noted the very low heteroplasmy levels reported in the proband’s leukocytes was unusual given the technology at the time, therefore this was not considered a de novo occurrence. Given no additional family members were tested, segregation evidence (PP1) could not be applied. There are no additional reported de novo occurrences of this variant to our knowledge. Computational predictors are not applicable for this variant type precluding consideration for PP3 or BP4. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). This 15 base pair microdeletion results in loss of the last 167 amino acids (64% of the protein, PVS1_strong). Single fiber testing showed higher levels of the variant in COX-negative non-RRF fibers (97.4 ± 1.4%) and in COX-negative RRF (98.6 ± 0.8%) than in COX-positive fibers (25.2 ± 25.1%; PS3_supporting; PMID: 8630495). In summary, this variant meets criteria to be classified as likely pathogenic for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on February 26, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM2_supporting, PS3_supporting, PVS1_strong. -

Mitochondrial complex IV deficiency, nuclear type 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 01, 1996

- -

Mitochondrial complex IV deficiency with recurrent myoglobinuria Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 01, 1996

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs267606612; hg19: chrM-9480;