M-8296-A-G

Variant names:

• chrM-8296-A-G
• rs118192102
• unassigned_transcript_4803:c.2A>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP3

This summary comes from the ClinGen Evidence Repository: The m.8296A>G variant in MT-TK has been reported in 18 unrelated individuals with primary mitochondrial disease with varying phenotypes (diabetes, hypertrophic cardiomyopathy, optic atrophy, sensorineural hearing loss, and generalized epilepsy; 10 subjects reported in PMIDs: 9802769, 9571188, 10525672; additional subjects reported in PMIDs: 10737988, 12504210, 18651333, 20143911, 37573175), however analyses for other genetic etiologies were limited in these affected individuals precluding their inclusion in this curation. The variant was present in some affected individuals at homoplasmy and in others at heteroplasmy. In at least one family, the variant was present at homoplasmy in the proband and in his healthy mother and sister (PMID:18651333). There are no reported de novo occurrences to our knowledge. This variant is present in population databases and is seen in individuals from several different haplogroups (MITOMAP: 0.061%, 38/61,883; gnomAD v3.1.2: 0.044%, 25/56,432 homoplasmic occurrences, one heteroplasmic occurrence; Helix: 0.048%, 94/195,893 homoplasmic occurrences). The computational predictor MitoTIP suggests this variant is pathogenic (72.3 percentile) and HmtVAR predicts it to be pathogenic score of 0.85 (PP3). Single fiber testing showed similar levels of the variant in COX-negative ragged red fibers and normal fibers (PMID:9932960), and cybrid studies showed no significant differences from wild type (PMID:11857739). 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 February 4, 2025. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID:32906214): PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA120557/MONDO:0044970/015

• Frequency: Mitomap GenBank: 𝑓 0.00060 (AC: 38)
• Consequence: TRNK unassigned_transcript_4803 missense
• Scores: Mitotip Uncertain 16
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:1 B:1 O:1 DMDF-/-MERRF-/-HCM-/-epilepsy-/-hearing-loss
• Conservation: PhyloP100: 1.81
• Publications: 4 publications found

Genes affected

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

MT-ATP6 (HGNC:7414): (mitochondrially encoded ATP synthase 6) Contributes to proton-transporting ATP synthase activity, rotational mechanism. Involved in mitochondrial ATP synthesis coupled proton transport. Part of mitochondrial proton-transporting ATP synthase complex. Implicated in Leber hereditary optic neuropathy; NARP syndrome; Parkinson's disease; multiple sclerosis; and systemic lupus erythematosus. [provided by Alliance of Genome Resources, Apr 2022]

MT-ATP8 (HGNC:7415): (mitochondrially encoded ATP synthase 8) Contributes to proton-transporting ATP synthase activity, rotational mechanism. Involved in mitochondrial ATP synthesis coupled proton transport. Part of mitochondrial proton-transporting ATP synthase complex. Implicated in multiple sclerosis and urinary bladder cancer. [provided by Alliance of Genome Resources, Apr 2022]

MT-CO2 (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]

MT-CO2 Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: Mitochondrial Classification: DEFINITIVE Submitted by: ClinGen
• cytochrome-c oxidase deficiency disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• MELAS syndrome

  Inheritance: Mitochondrial Classification: SUPPORTIVE Submitted by: Orphanet
• Leigh syndrome

  Inheritance: Mitochondrial Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PP3: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRNK	unassigned_transcript_4803	c.2A>G	p.His1Arg	missense_variant	Exon 1 of 1
ATP6	unassigned_transcript_4805	c.-231A>G		upstream_gene_variant
ATP8	unassigned_transcript_4804	c.-70A>G		upstream_gene_variant
COX2	unassigned_transcript_4802	c.*27A>G		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MT-TK	ENST00000387421.1	n.2A>G		non_coding_transcript_exon_variant	Exon 1 of 1	6
MT-ATP6	ENST00000361899.2	c.-231A>G		upstream_gene_variant		6		ENSP00000354632.2
MT-ATP8	ENST00000361851.1	c.-70A>G		upstream_gene_variant		6		ENSP00000355265.1
MT-CO2	ENST00000361739.1	c.*27A>G		downstream_gene_variant		6		ENSP00000354876.1

Frequencies

Mitomap GenBank AF: 0.00060 AC: 38

Gnomad homoplasmic AF: 0.00044 AC: 25 AN: 56432

Gnomad heteroplasmic AF: 0.000018 AC: 1 AN: 56432

Alfa AF: 0.000212 Hom.: 1

Mitomap

Disease(s): DMDF-/-MERRF-/-HCM-/-epilepsy-/-hearing-loss

Status: Reported

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1 Benign:1 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

MELAS syndrome Benign:1 Other:1

Jul 12, 2019

Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The NC_012920.1:m.8296A>G variant in MT-TK gene is interpreted to be a Benign variant based on the modified ACMG guidelines (unpublished). This variant meets the following evidence codes reported in the guidelines: BS1, BS2 -

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Diabetes-deafness syndrome maternally transmitted Pathogenic:1

Apr 17, 1998

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Mitochondrial disease Uncertain:1

Feb 04, 2025

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

Significance: Uncertain significance

Review Status: reviewed by expert panel

Collection Method: curation

The m.8296A>G variant in MT-TK has been reported in 18 unrelated individuals with primary mitochondrial disease with varying phenotypes (diabetes, hypertrophic cardiomyopathy, optic atrophy, sensorineural hearing loss, and generalized epilepsy; 10 subjects reported in PMIDs: 9802769, 9571188, 10525672; additional subjects reported in PMIDs: 10737988, 12504210, 18651333, 20143911, 37573175), however analyses for other genetic etiologies were limited in these affected individuals precluding their inclusion in this curation. The variant was present in some affected individuals at homoplasmy and in others at heteroplasmy. In at least one family, the variant was present at homoplasmy in the proband and in his healthy mother and sister (PMID: 18651333). There are no reported de novo occurrences to our knowledge. This variant is present in population databases and is seen in individuals from several different haplogroups (MITOMAP: 0.061%, 38/61,883; gnomAD v3.1.2: 0.044%, 25/56,432 homoplasmic occurrences, one heteroplasmic occurrence; Helix: 0.048%, 94/195,893 homoplasmic occurrences). The computational predictor MitoTIP suggests this variant is pathogenic (72.3 percentile) and HmtVAR predicts it to be pathogenic score of 0.85 (PP3). Single fiber testing showed similar levels of the variant in COX-negative ragged red fibers and normal fibers (PMID: 9932960), and cybrid studies showed no significant differences from wild type (PMID: 11857739). 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 February 4, 2025. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PP3. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Mitotip	Uncertain	16
Hmtvar	Pathogenic	0.85
PhyloP100		1.8

Other links and lift over

dbSNP: rs118192102; hg19: chrM-8297;