rs199474827

Variant names:

• chrM-7671-T-A
• rs199474827
• ENST00000361739.1:c.86T>A

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM6_Supporting PS3_Supporting PM2 PP3

This summary comes from the ClinGen Evidence Repository: The m.7671T>A (p.M29K) variant in MT-CO2 has been reported in two unrelated individuals with primary mitochondrial disease to date. The first individual was a 14 year old male with proximal myopathy, lactic acidosis, and a five year history of muscle weakness and fatigue. Skeletal muscle biopsies revealed severe COX deficiency, increased SDH staining, and absence of ragged red fibers. Variant heteroplasmy was 90% in muscle and 4.5% - 6% in blood. The second individual was a 48 year old male of European ancestry with mitochondrial myopathy characterized by progressive weakness. Serum creatine kinase levels were elevated and muscle biopsy revealed scattered COX-negative fibers with increased SDH staining. This variant was observed at 52% heteroplasmy, presumably in the muscle sample (PMID:32800583). Haplogroup information was not reported for both cases precluding consideration for PS4. This variant occurred de novo in one individual (absent in blood from mother; PM6_supporting, PMID:10486321). Single fiber testing showed higher levels of the variant in COX negative fibers (81%, n=13) than in COX positive fibers (45%, n=4), p<0.01 (PS3_supporting, PMID:10486321). The computational predictors APOGEE1 and APOGEE2 give a consensus rating of pathogenic with raw scores of 0.90 and 0.942, respectively (Min=0, Max=1), which predict a damaging effect on gene function (PP3). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). In summary, this variant meets criteria to be classified as uncertain significance 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 November 28, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID:32906214): PM6_supporting, PS3_supporting, PM2_supporting, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA120605/MONDO:0044970/015

• Frequency: Mitomap GenBank: Absent
• Consequence: MT-CO2 ENST00000361739.1 missense
• Scores: Apogee2 Pathogenic 0.94
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:1 MM
• Conservation: PhyloP100: 4.82
• Publications: 11 publications found

Genes affected

MT-CO2 (HGNC:7421): (mitochondrially encoded cytochrome c oxidase II) Contributes to cytochrome-c oxidase activity. Predicted to be involved in mitochondrial electron transport, cytochrome c to oxygen and positive regulation of vasoconstriction. Located in mitochondrial inner membrane. Part of respiratory chain complex IV. Biomarker of Huntington's disease and stomach cancer. [provided by Alliance of Genome Resources, Apr 2022]

MT-CO1 (HGNC:7419): (mitochondrially encoded cytochrome c oxidase I) Contributes to cytochrome-c oxidase activity. Predicted to be involved in electron transport coupled proton transport and mitochondrial electron transport, cytochrome c to oxygen. Part of mitochondrial respiratory chain complex III and mitochondrial respiratory chain complex IV. [provided by Alliance of Genome Resources, Apr 2022]

TRNS1 (HGNC:7497): (mitochondrially encoded tRNA serine 1 (UCN))

TRND (HGNC:7478): (mitochondrially encoded tRNA aspartic acid)

TRND Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: Mitochondrial Classification: MODERATE Submitted by: ClinGen

ACMG classification

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

• PS3: 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.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COX2	unassigned_transcript_4802	c.86T>A	p.Met29Lys	missense_variant	Exon 1 of 1
TRNS1	unassigned_transcript_4800	c.-157A>T		upstream_gene_variant
COX1	unassigned_transcript_4799	c.*226T>A		downstream_gene_variant
TRND	unassigned_transcript_4801	c.*86T>A		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MT-CO2	ENST00000361739.1	c.86T>A	p.Met29Lys	missense_variant	Exon 1 of 1	6		ENSP00000354876.1
MT-CO1	ENST00000361624.2	c.*226T>A		downstream_gene_variant		6		ENSP00000354499.2
MT-TS1	ENST00000387416.2	n.-157A>T		upstream_gene_variant		6
MT-TD	ENST00000387419.1	n.*86T>A		downstream_gene_variant		6

Frequencies

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

Mitomap

Disease(s): MM

Status: Reported-[VUS]

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Mitochondrial complex IV deficiency, nuclear type 1 Pathogenic:1

Oct 01, 1999

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Mitochondrial disease Uncertain:1

Nov 28, 2023

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

Significance: Uncertain significance

Review Status: reviewed by expert panel

Collection Method: curation

The m.7671T>A (p.M29K) variant in MT-CO2 has been reported in two unrelated individuals with primary mitochondrial disease to date. The first individual was a 14 year old male with proximal myopathy, lactic acidosis, and a five year history of muscle weakness and fatigue. Skeletal muscle biopsies revealed severe COX deficiency, increased SDH staining, and absence of ragged red fibers. Variant heteroplasmy was 90% in muscle and 4.5% - 6% in blood. The second individual was a 48 year old male of European ancestry with mitochondrial myopathy characterized by progressive weakness. Serum creatine kinase levels were elevated and muscle biopsy revealed scattered COX-negative fibers with increased SDH staining. This variant was observed at 52% heteroplasmy, presumably in the muscle sample (PMID: 32800583). Haplogroup information was not reported for both cases precluding consideration for PS4. This variant occurred de novo in one individual (absent in blood from mother; PM6_supporting, PMID: 10486321). Single fiber testing showed higher levels of the variant in COX negative fibers (81%, n=13) than in COX positive fibers (45%, n=4), p<0.01 (PS3_supporting, PMID: 10486321). The computational predictors APOGEE1 and APOGEE2 give a consensus rating of pathogenic with raw scores of 0.90 and 0.942, respectively (Min=0, Max=1), which predict a damaging effect on gene function (PP3). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). In summary, this variant meets criteria to be classified as uncertain significance 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 November 28, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM6_supporting, PS3_supporting, PM2_supporting, PP3. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Apogee2	Pathogenic	0.94
Hmtvar	Pathogenic	0.86
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Uncertain	0.040	T
PhyloP100		4.8
GERP RS		5.2
Varity_R		0.41

Other links and lift over

dbSNP: rs199474827; hg19: chrM-7672;