chrM-9531-A-AC

Variant names:

• chrM-9531-A-AC
• rs267606614
• ENST00000362079.2:c.331dupC

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.9537dupC variant in MT-CO3 has been reported in one individual with primary mitochondrial disease to date (PMID:11063732), in an 11-year-old girl with Leigh syndrome spectrum disorder. Progressive spastic paraparesis, ophthalmoplegia, and moderate intellectual disability were noted at age four years, as was severe lactic acidosis and lesions in the putamina on brain imaging. The variant was reported as being “virtually homoplasmic” in skeletal muscle, fibroblasts, and lymphocytes. The variant was not detected in lymphocytes from her unaffected brother and maternal grandmother, and was similarly absent in lymphocytes, hair, and oral epithelial cells in her mother. However, technology at the time was limited in detecting low heteroplasmy levels. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). There are no in silico predictors for this type of variant in mitochondrial DNA. This frameshift variant at amino position 111 creates a stop codon three positions downstream, resulting in a significant (57%) truncation of the MT-CO3 protein (PVS1_strong). Cybrid studies supported the functional impact of this variant (PMID:11063732), as did studies in colonic crypt stem cells (PMID:14597761; PS3_supporting). 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 April 22, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID:32906214): PVS1_strong, PM2_supporting, PS3_supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA120602/MONDO:0044970/015

• Frequency: Mitomap GenBank: Absent
• Consequence: MT-CO3 ENST00000362079.2 frameshift
• Clinical Significance: Likely pathogenic reviewed by expert panel P:2 O:1 Leigh-Disease
• Conservation: PhyloP100: 7.62
• Publications: 2 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000362079.2. 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
There are no transcript annotations for this variant.

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MT-CO3	ENST00000362079.2	TSL:6	c.331dupC	p.Gln111fs	frameshift	Exon 1 of 1	ENSP00000354982.2	P00414

Frequencies

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

Mitomap

Disease(s): Leigh-Disease

Status: Reported

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
1	-	-	Mitochondrial complex IV deficiency, nuclear type 1 (1)
1	-	-	Mitochondrial disease (1)
-	-	-	Leigh syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.6

Other links and lift over

dbSNP: rs267606614; hg19: chrM-9532;