rs199476129

Variant names:

• chrM-5920-G-A
• rs199476129
• ENST00000361624.2:c.17G>A

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.5920G>A (p.W6Ter) variant in MT-CO1 has been reported in one individual to date, in a man with childhood onset myopathy, and myoglobinuria first noted in his 20s (case first reported in PMID:10980727, also reported in PMIDs: 11506394, 11782982). His muscle biopsy showed scattered ragged red fibers (RRF) that stained intensely for SDH but not COX and numerous COX-negative/COX-deficient non-RRF. Immunohistochemistry showed markedly reduced immunostaining with antibodies to COX I and COX II, but normal reaction with antibodies to COX IV and COX VI. He had complex IV deficiency with activity being 32% controls. The variant was present at 61% heteroplasmy in muscle and was absent in blood and fibroblasts. As this is the only case reported to date, PS4 could not be applied. The variant was absent in blood from his mother and sister, however given it was also absent in the proband’s blood, it is not conclusive the variant arose de novo. 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 variant results in loss of the last 507 amino acids (99% of the protein, PVS1_strong). Single fiber testing showed that the variant was present in all COX-deficient fibers (n=15) and that the mean mutation load in affected fibers was 65% (SD, 32.6%). The variant was only detected in six of 25 COX-positive fibers tested, and the mutational load in COX-positive fibers was 5% (SD, 11.2%; PS3_supporting; PMID:10980727). 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 January 22, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID:32906214): PM2_supporting, PS3_supporting, PVS1_strong. LINK:https://erepo.genome.network/evrepo/ui/classification/CA120613/MONDO:0044970/015

• Frequency: Mitomap GenBank: Absent
• Consequence: MT-CO1 ENST00000361624.2 stop_gained
• Clinical Significance: Likely pathogenic reviewed by expert panel P:2 Myoglobinuria-/-EXIT
• Conservation: PhyloP100: 6.55
• Publications: 4 publications found

Genes affected

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]

TRNN (HGNC:7493): (mitochondrially encoded tRNA asparagine)

TRNC (HGNC:7477): (mitochondrially encoded tRNA cysteine)

TRNY (HGNC:7502): (mitochondrially encoded tRNA tyrosine)

TRNY Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: Mitochondrial Classification: DEFINITIVE 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
COX1	unassigned_transcript_4799	c.17G>A	p.Trp6*	stop_gained	Exon 1 of 1
TRNN	unassigned_transcript_4796	c.-191C>T		upstream_gene_variant
TRNC	unassigned_transcript_4797	c.-94C>T		upstream_gene_variant
TRNY	unassigned_transcript_4798	c.-29C>T		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MT-CO1	ENST00000361624.2	c.17G>A	p.Trp6*	stop_gained	Exon 1 of 1	6		ENSP00000354499.2
MT-TN	ENST00000387400.1	n.-191C>T		upstream_gene_variant		6
MT-TC	ENST00000387405.1	n.-94C>T		upstream_gene_variant		6
MT-TY	ENST00000387409.1	n.-29C>T		upstream_gene_variant		6

Frequencies

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

Mitomap

Disease(s): Myoglobinuria-/-EXIT

Status: Cfrm-[LP]

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: reviewed by expert panel

Submissions by phenotype

Myoglobinuria, recurrent Pathogenic:1

Sep 12, 2000

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Mitochondrial disease Pathogenic:1

Jan 22, 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.5920G>A (p.W6Ter) variant in MT-CO1 has been reported in one individual to date, in a man with childhood onset myopathy, and myoglobinuria first noted in his 20s (case first reported in PMID: 10980727, also reported in PMIDs: 11506394, 11782982). His muscle biopsy showed scattered ragged red fibers (RRF) that stained intensely for SDH but not COX and numerous COX-negative/COX-deficient non-RRF. Immunohistochemistry showed markedly reduced immunostaining with antibodies to COX I and COX II, but normal reaction with antibodies to COX IV and COX VI. He had complex IV deficiency with activity being 32% controls. The variant was present at 61% heteroplasmy in muscle and was absent in blood and fibroblasts. As this is the only case reported to date, PS4 could not be applied. The variant was absent in blood from his mother and sister, however given it was also absent in the proband’s blood, it is not conclusive the variant arose de novo. 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 variant results in loss of the last 507 amino acids (99% of the protein, PVS1_strong). Single fiber testing showed that the variant was present in all COX-deficient fibers (n=15) and that the mean mutation load in affected fibers was 65% (SD, 32.6%). The variant was only detected in six of 25 COX-positive fibers tested, and the mutational load in COX-positive fibers was 5% (SD, 11.2%; PS3_supporting; PMID: 10980727). 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 January 22, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM2_supporting, PS3_supporting, PVS1_strong. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.42	D
PhyloP100		6.5
GERP RS		5.2

Other links and lift over

dbSNP: rs199476129; hg19: chrM-5921;