M-8306-T-C

Variant names:

• chrM-8306-T-C
• unassigned_transcript_4803:c.12T>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

Variant has been reported in ClinVar as Uncertain significance (★★★).

• Frequency: Mitomap GenBank: Absent
• Consequence: TRNK synonymous
• Scores: Mitotip Pathogenic 18
• Clinical Significance: Uncertain significance reviewed by expert panel U:1 Severe-adult-onset-multisymptom-myopathy-/-Myoclonic-epilepsy
• Conservation: PhyloP100: 4.60

Genes affected

TRNK (HGNC:7489): (mitochondrially encoded tRNA lysine)

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: No frequency data in Mitomap. Probably very rare.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRNK	unassigned_transcript_4803	c.12T>C	p.Ala4Ala	synonymous_variant	Exon 1 of 1
COX2	unassigned_transcript_4802	c.*37T>C		downstream_gene_variant

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

Severe-adult-onset-multisymptom-myopathy-/-Myoclonic-epilepsy

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Mitochondrial disease Uncertain:1

Uncertain significance, reviewed by expert panel

curation

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

Oct 24, 2022

The m.8306T>C variant in MT-TK has been reported in three individuals with primary mitochondrial disease (PS4_supporting; PMIDs: 22925535, 23847141, 34354612). The first case was reported in 2012 and was a man with onset at 30 years with progressive concerns over time. His medical concerns included muscle weakness, muscle atrophy, cardiac arrhythmia, dysphagia, hearing loss, and insulin resistance. Muscle biopsy showed ragged red fibers and COX-negative fibers, and muscle CT showed bilateral atrophy with fatty replacement. The variant was present at 98% in muscle, 30% in hair roots, 27% in urine, 17% in buccal, and 5% in blood (PMID: 22925535). The other two cases were part of cohort reports with limited clinical details provided (PMIDs: 23847141, 34354612). This variant was reported in additional individuals in one publication (PMID: 29663531) however these cases were excluded from this curation as it was unclear which case(s) had this variant. Furthermore, several cases in this series came from consanguineous families and other nuclear genetic etiologies were not excluded (PMID: 29663531). There are no large families reported in the medical literature to consider for evidence of segregation. While this variant was absent in blood, buccal, hair, and urine from healthy siblings of one proband, the mother was not available for testing to confirm a de novo occurrence (PMID: 22925535). The computational predictor MitoTIP suggests this variant is pathogenic (88.8 percentile) and HmtVAR predicts it to be pathogenic score of 0.7 (PP3). This variant is absent in the Genbank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). Single fiber testing showed higher levels of the variant in COX-negative fibers (97.4% +/- 1.2, n=11) than in COX-positive fibers (18.8% +/- 9.2, n+10), p<0.0001 (PS3_supporting, PMID: 22925535). 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 October 24, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_supporting, PM2_supporting, PP3, PS3_supporting. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Mitotip	Pathogenic	18
Hmtvar	Pathogenic	0.70

Splicing

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chrM-8307;