Submissions for variant m.12258C>A

Minimum review status:		Collection method:
Minimum conflict level: Report conflict between different conditions
		ClinVar version:

Total submissions: 3

Download table as spreadsheet

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen	RCV003162227	SCV003915447	likely pathogenic	Mitochondrial disease	2023-03-28	reviewed by expert panel	curation	The m.12258C>A variant in MT-TS2 gene has been reported in two unrelated individuals with primary mitochondrial disease (PS4_supporting). Family members of both probands were also affected. The age of onset was in adulthood and ranged from the 20s to 60s. Features seen in affected individuals include diabetes, cataracts, retinitis pigmentosa, hearing loss, and cerebellar ataxia (PMIDs: 9792552, 10090882). This variant segregated with disease in multiple affected members in both families and several healthy family members had lower to undetectable levels of the variant (PP1_moderate; PMIDs: 10090882, 9792552). There are no reported de novo occurrences of this variant to our knowledge. There is one occurrence in population databases (one occurrence in Mitomap GenBank sequences, absent in gnomAD v3.1.2 and Helix dataset). Although there is one occurrence, the frequency is still low (PM2_supporting). The computational predictor MitoTIP suggests this variant is pathogenic (95.3 percentile) and HmtVAR predicts it to be pathogenic with a score of 0.4 (PP3). Single fiber studies support the functional impact of this variant (PS3_supporting) as the level of variant in COX-positive fibers ranged from 23-71%, while in COX-negative fibers was present at >85% heteroplasmy (PMID: 9792552). 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 28, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_supporting, PP1_moderate, PM2_supporting, PP3, PS3_supporting.
OMIM	RCV000010170	SCV000030391	pathogenic	Cerebellar ataxia, cataract, and diabetes mellitus	1999-04-01	no assertion criteria provided	literature only
OMIM	RCV000010171	SCV000030392	pathogenic	Retinitis pigmentosa-deafness syndrome	1999-04-01	no assertion criteria provided	literature only

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.