rs199474829

Variant names:

• chrM-7896-G-A
• rs199474829
• unassigned_transcript_4802:c.311G>A

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 Pathogenic (★★★).

• Frequency: Mitomap GenBank: Absent
• Consequence: COX2 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:2 Multisystem-Disorder
• Conservation: PhyloP100: 7.70

Genes affected

COX2 (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]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM2: No frequency data in Mitomap. Probably very rare.
• PP5: Variant M-7896-G-A is Pathogenic according to our data. Variant chrM-7896-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 9662.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COX2	unassigned_transcript_4802	c.311G>A	p.Trp104*	stop_gained	Exon 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	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

Multisystem-Disorder

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: reviewed by expert panel

Submissions by phenotype

Mitochondrial complex IV deficiency, nuclear type 1 Pathogenic:1

Sep 01, 2001

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Mitochondrial disease Pathogenic:1

Feb 12, 2024

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

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The m.7896G>A (p.W104Ter) variant in MT-CO2 has been reported in one individual to date (PMID: 11558799), in a three-year-old child with psychomotor delay, failure to thrive, and cardiac hypertrophy from infancy who later developed cerebral atrophy and pigmentary retinopathy. Complex IV deficiency was noted in muscle. The variant was present at 76% heteroplasmy in muscle, 67% in blood, and 60% in fibroblasts. The variant was undetectable in blood from her mother and sister (PM6_supporting). There are no additional 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). There are no in silico predictors for this type of variant in mitochondrial DNA. This variant results in a significant truncation (52%) of the MT-CO2 protein (PVS1_strong). There were several compelling studies performed detailing functional validation (PS3_supporting). Activities and assembly of complexes I and IV (and of any COX-containing supercomplexes) were impaired in cybrid cell lines with the variant present at homoplasmy (PMID: 22342700). Single fiber testing showed higher levels of the variant in COX-deficient fibers (n = 9; 70.8 ± 8.1%) than in COX-positive fibers (n = 10; 17.6 ± 17.8%; p < 0.0001; PMID: 11558799). Immunoblot analysis in muscle from the proband revealed a 53% reduction of the COX II polypeptide and a 48% reduction of COX I polypeptide compared to controls (PMID: 11558799). In summary, this variant meets criteria to be classified as likely pathogenic for primary mitochondrial disease however, after extensive discussion, this Expert Panel elected to modify the classification to pathogenic given the compelling functional validation and variant type. We note that some experts on this panel felt likely pathogenic was the more appropriate classification. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on February 12, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM6_supporting, PS3_supporting, PM2_supporting, PVS1_strong. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.44	D
GERP RS		5.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs199474829; hg19: chrM-7897;