Submissions for variant NC_012920.1(MT-CYB):m.4298G>A

dbSNP: rs1603219395

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen	RCV003153874	SCV003842277	uncertain significance	Mitochondrial disease	2022-12-12	reviewed by expert panel	curation	The m.4298G>A variant in MT-TI has been reported in two unrelated adults with primary mitochondrial disease. Chronic progressive external ophthalmoplegia (CPEO) and multiple sclerosis (MS) were seen in one individual (PMID: 9473477) and the second individual had rhabdomyolysis, myoglobinuria, and myalgia after fasting or exercise in addition to muscle weakness and unstable gait (PMID: 16120360). This variant was seen in varying degrees of heteroplasmy in these individuals in muscle, urine, and hair roots by PCR/RFLP, but was not observed in blood (PS4_supporting). Family member testing was performed in one case and the variant was undetectable in the proband’s mother’s blood, however the variant was also undetectable in the proband’s blood precluding confirmation of a de novo occurrence (PMID: 16120360). There are no large families reported in the medical literature to consider for evidence of segregation. The computational predictor MitoTIP suggests this variant is pathogenic, scoring in the 63.5 percentile; HmtVAR also predicts it to be pathogenic, scoring in the 75.0 percentile (PP3). The m.4298G>A variant is absent in the GenBank dataset, the Helix dataset, and gnomAD v3.1.2 (PM2_supporting). Single-fiber testing (PMID: 9473477) showed 78% heteroplasmy in COX-negative fibers and 27% in COX-positive fibers. Aminoacylation assays showed that the capacity for aminoacylation of tRNAs with this variant was virtually nil (<0.1%) and the observed aminoacylation deficiency was rescued by an engineered compensatory variant (PMID: 12655007). This and other results led the authors to propose that the functional defect caused by this mutation is due to fragility of the tRNA structure (PS3_supporting). In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. We note that two experts on this panel felt likely pathogenic was a more appropriate classification given the functional evidence of impact however the majority agreed with uncertain significance. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on December 12, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied: PS4_supporting, PS3_supporting, PP3, PM2_supporting.
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	RCV000850720	SCV000992953	pathogenic	Juvenile myopathy, encephalopathy, lactic acidosis AND stroke	2019-07-12	criteria provided, single submitter	clinical testing	The NC_012920.1:m.4298G>A variant in MT-TI 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