rs199476129

chrM-5920-G-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The ENST00000361624.2(MT-CO1):c.17G>A(p.Trp6Ter) variant causes a stop gained change. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★★).

• 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

Genes affected

COX1 (HGNC:):

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]

MT-TY (HGNC:7502): (mitochondrially encoded tRNA tyrosine)

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 4 pathogenic variants in the truncated region.
• PM2: No frequency data in Mitomap. Probably very rare.
• PP5: Variant M-5920-G-A is Pathogenic according to our data. Variant chrM-5920-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 9669.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COX1	COX1.1	c.17G>A	p.Trp6Ter	stop_gained	1/1
TRNY	TRNY.1			upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MT-CO1	ENST00000361624.2	c.17G>A	p.Trp6Ter	stop_gained	1/1			P1
MT-TY	ENST00000387409.1			upstream_gene_variant

Frequencies

GnomAD4 exome Cov.: 0

We have no GnomAD4 genomes data on this position. Probably position not covered by the project.

Mitomap

Myoglobinuria-/-EXIT

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: reviewed by expert panel

Submissions by phenotype

Myoglobinuria, recurrent Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 12, 2000

- -

Mitochondrial disease Pathogenic:1

Likely pathogenic, reviewed by expert panel

curation

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

Jan 22, 2024

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
MutationTaster	Benign	1.0	A
GERP RS		5.2

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs199476129; hg19: chrM-5921;