M-9952-G-A

Variant names:

• chrM-9952-G-A
• rs267606613
• ENST00000362079.2:c.746G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 5 ACMG points: 5P and 0B. PVS1_Moderate PM6 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The m.9952G>A (p.W249Term) variant in MT-CO3 has been reported in one individual with mitochondrial disease to date, in a 36-year-old woman with encephalopathy, myopathy, exercise-induced myalgia, muscle weakness, and migraines, with onset of symptoms at age 17 years (PMID:9634511). Muscle biopsy showed reduced COX activity and decreased complex IV activity. The variant was present at 57% heteroplasmy in muscle and was undetectable in blood and skin. The variant was absent in muscle from her mother (PM6; PMID:9634511). This variant causes a premature stop in the MT-CO3 gene resulting in truncation of 5% of the protein (PVS1_moderate). This variant is absent in the MITOMAP GenBank dataset, gnomAD v3.1.2, and the Helix dataset (PM2_supporting). There are no in silico predictors for this type of variant in mitochondrial DNA. Single fiber testing showed higher levels of the variant in COX negative fibers (56.2%, n=24) than in COX positive fibers (10.1%, n=21), p<0.0002 (PS3_supporting, PMID:9634511). 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): PM6, PVS1_moderate, PM2_supporting, PS3_supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA120601/MONDO:0044970/015

• Frequency: Mitomap GenBank: Absent
• Consequence: MT-CO3 ENST00000362079.2 stop_gained
• Clinical Significance: Likely pathogenic reviewed by expert panel P:2 Mitochondrial-Encephalopathy
• 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-ND3 (HGNC:7458): (mitochondrially encoded NADH dehydrogenase 3) Enables NADH dehydrogenase (ubiquinone) activity. Involved in mitochondrial electron transport, NADH to ubiquinone. Part of mitochondrial respiratory chain complex I. Implicated in Leber hereditary optic neuropathy; Leigh disease; and Parkinson's disease. [provided by Alliance of Genome Resources, Apr 2022]

TRNG (HGNC:7486): (mitochondrially encoded tRNA glycine)

TRNG Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: Mitochondrial Classification: MODERATE Submitted by: ClinGen

ACMG classification

Our verdict: Likely_pathogenic. The variant received 5 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM6: 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MT-CO3	ENST00000362079.2	TSL:6	c.746G>A	p.Trp249*	stop_gained	Exon 1 of 1	ENSP00000354982.2
	MT-ND3	ENST00000361227.2	TSL:6	c.-107G>A		upstream_gene	N/A	ENSP00000355206.2
	MT-TG	ENST00000387429.1	TSL:6	n.-39G>A		upstream_gene	N/A

Frequencies

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

Alfa AF: 0.00 Hom.: 0

Mitomap

Disease(s): Mitochondrial-Encephalopathy

Status: Reported

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: reviewed by expert panel

Submissions by phenotype

Mitochondrial complex IV deficiency, nuclear type 1 Pathogenic:1

Jul 01, 1998

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.9952G>A (p.W249Term) variant in MT-CO3 has been reported in one individual with mitochondrial disease to date, in a 36-year-old woman with encephalopathy, myopathy, exercise-induced myalgia, muscle weakness, and migraines, with onset of symptoms at age 17 years (PMID: 9634511). Muscle biopsy showed reduced COX activity and decreased complex IV activity. The variant was present at 57% heteroplasmy in muscle and was undetectable in blood and skin. The variant was absent in muscle from her mother (PM6; PMID: 9634511). This variant causes a premature stop in the MT-CO3 gene resulting in truncation of 5% of the protein (PVS1_moderate). This variant is absent in the MITOMAP GenBank dataset, gnomAD v3.1.2, and the Helix dataset (PM2_supporting). There are no in silico predictors for this type of variant in mitochondrial DNA. Single fiber testing showed higher levels of the variant in COX negative fibers (56.2%, n=24) than in COX positive fibers (10.1%, n=21), p<0.0002 (PS3_supporting, PMID: 9634511). 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): PM6, PVS1_moderate, PM2_supporting, PS3_supporting.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.69	D
PhyloP100		7.7
GERP RS		5.1

Other links and lift over

dbSNP: rs267606613; hg19: chrM-9953;