rs267606612

Variant names:

• chrM-9479-TTTTTTCTTCGCAGGA-T
• rs267606612
• ENST00000362079.2:c.281_295delTCGCAGGATTTTTCT

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_Strong PS3_Supporting PM2_Supporting

This summary comes from the ClinGen Evidence Repository: 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. LINK:https://erepo.genome.network/evrepo/ui/classification/CA120600/MONDO:0044970/015

• Frequency: Mitomap GenBank: Absent
• Consequence: MT-CO3 ENST00000362079.2 disruptive_inframe_deletion
• Clinical Significance: Likely pathogenic reviewed by expert panel P:3 Myoglobinuria
• Conservation: PhyloP100: 7.73
• Publications: 1 publications found

Genes affected

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]

MT-CO3 Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: Mitochondrial Classification: DEFINITIVE Submitted by: ClinGen
• hereditary recurrent myoglobinuria

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• cytochrome-c oxidase deficiency disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Leber hereditary optic neuropathy

  Inheritance: Mitochondrial Classification: SUPPORTIVE Submitted by: Orphanet
• Leigh syndrome

  Inheritance: Mitochondrial Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COX3	unassigned_transcript_4806	c.281_295delTCGCAGGATTTTTCT	p.Phe94_Phe98del	disruptive_inframe_deletion	Exon 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MT-CO3	ENST00000362079.2	c.281_295delTCGCAGGATTTTTCT	p.Phe94_Phe98del	disruptive_inframe_deletion	Exon 1 of 1	6		ENSP00000354982.2

Frequencies

Mitomap GenBank The variant is not present, suggesting it is rare .

Mitomap

Disease(s): Myoglobinuria

Status: Reported-(alt-loc)

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: reviewed by expert panel

Submissions by phenotype

Mitochondrial complex IV deficiency, nuclear type 1 Pathogenic:1

Apr 01, 1996

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Mitochondrial disease Pathogenic:1

Feb 26, 2024

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

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

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 with recurrent myoglobinuria Pathogenic:1

Apr 01, 1996

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.7

Other links and lift over

dbSNP: rs267606612; hg19: chrM-9480;