Submissions for variant NC_012920.1(MT-TK):m.8363G>A

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Minimum conflict level: Report conflict between different conditions
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Total submissions: 6

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen	RCV003162232	SCV003915454	likely pathogenic	Mitochondrial disease	2023-03-13	reviewed by expert panel	curation	The m.8363G>A variant in MT-TK has been reported in at least 30 individuals with primary mitochondrial disease from 12 kindreds. Features seen in affected individuals include Leigh syndrome and myoclonic epilepsy with ragged red fibers (MERRF), as well as myopathy, peripheral neuropathy, ataxia, cardiomyopathy, sensorineural hearing loss, ophthalmoplegia, and lipomas. Heteroplasmy levels of this variant in affected individuals is variable, ranging from 40-97% (PS4_moderate; PMIDs: 8651277, 9052804, 10868777, 11108511, 19278689, 18319067, 19370763, 10102446, 16326995, 9932960). This variant segregated with disease in multiple affected family members in multiple families and several healthy family members had lower to undetectable levels (PP1_moderate; PMIDs: 9052804, 10868777, 10102446, 9932960). There are no confirmed de novo occurrences of this variant to our knowledge. The computational predictor MitoTIP suggests this variant impacts the function of this tRNA with a score of 94.3 percentile, as does HmtVar with a score of 0.75 (PP3). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). Single fiber testing and cybrid analysis further support the functional impact of this variant (PS3_suporting). Single fiber testing showed the variant was significantly higher in COX-negative ragged red fibers (n = 5; 97.3% ± 2.5) than in normal fibers (n = 5; 89.2 ± 8.3; p < 0.05; PMID: 9932960). Cybrid studies showed that clones with the variant present at homoplasmy had statistically significant decreases in Complex I, ATP synthase, and oxygen consumption (PMIDs: 15554876, 25909222). 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 13, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_moderate, PP3, PP1_moderate, PS3_supporting, PM2_supporting.
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	RCV000850961	SCV000993195	pathogenic	MELAS syndrome	2019-07-12	criteria provided, single submitter	clinical testing	The NC_012920.1:m.8363G>A variant in MT-TK gene is interpreted to be a Pathogenic variant based on the modified ACMG guidelines (unpublished). This variant meets the following evidence codes reported in the guidelines: PS3, PS5, PM7
Mendelics	RCV000850961	SCV002517703	pathogenic	MELAS syndrome	2022-05-04	criteria provided, single submitter	clinical testing
OMIM	RCV000010197	SCV000030420	pathogenic	Cardiomyopathy and Deafness	1996-05-01	no assertion criteria provided	literature only
GeneReviews	RCV000144004	SCV000188891	not provided	Leigh syndrome		no assertion provided	literature only
GeneReviews	RCV000192053	SCV000207616	not provided	MERRF syndrome		no assertion provided	literature only	Pathogenic variants identified in approximately 10% of persons w/MERRF

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