rs199474825

Positions:

• chrM-7587-T-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PP5_Very_Strong

In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★★).

• Frequency: Mitomap GenBank: Absent
• Consequence: COX2 start_lost
• Scores: Apogee2 Pathogenic 0.88
• Clinical Significance: Likely pathogenic reviewed by expert panel P:2 Mitochondrial-Encephalomyopathy
• Conservation: PhyloP100: 7.73

Genes affected

COX2 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM2: No frequency data in Mitomap. Probably very rare.
• PP5: Variant M-7587-T-C is Pathogenic according to our data. Variant chrM-7587-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 9658.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COX2	unassigned_transcript_4803	c.2T>C	p.Met1?	start_lost	1/1
TRND	unassigned_transcript_4802	c.*2T>C		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt

Frequencies

GnomAD4 exome Cov.: 0

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

Mitomap

Mitochondrial-Encephalomyopathy

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: reviewed by expert panel

Submissions by phenotype

Mitochondrial disease Pathogenic:1

Likely pathogenic, reviewed by expert panel

curation

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

Mar 11, 2024

The m.7587T>C (p.M1T) variant in MT-CO2 has been reported in one family with primary mitochondrial disease to date (PMID: 10205264). Affected individuals in this family include a 57-year-old woman with fatigue and unsteady gait and her more severely affected son who was nonambulatory and had cognitive impairment, optic atrophy, pigmentary retinopathy, and distal muscle wasting. The variant was present at 67% heteroplasmy in the muscle of the mother and at 91% in muscle of her affected son. There are no individuals reported with de novo occurrences of this variant to our knowledge. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.79 (Min=0, Max=1; APOGEE2 score is 0.875), which predicts a damaging effect on gene function (PP3). This initiation codon variant results in a significant truncation of the MT-CO2 protein (PVS1_strong). Single fiber testing showed higher levels of the variant in COX-negative (near homoplasmy) than in COX-positive fibers (17–52%; PS3_supporting, PMID: 10205264). 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 March 11, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PVS1_strong, PP3, PS3_supporting, PM2_supporting. -

Mitochondrial complex IV deficiency, nuclear type 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 01, 1999

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Apogee2	Pathogenic	0.88
Hmtvar	Pathogenic	0.79
BayesDel_addAF	Benign	-0.020	T
DEOGEN2	Benign	0.23	T
LIST_S2	Uncertain	0.90	D
PROVEAN	Pathogenic	-5.7	D
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
GERP RS		4.3
Varity_R		0.76

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs199474825; hg19: chrM-7588;