Submissions for variant NC_012920.1:m.10046T>C

dbSNP: rs876661357

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	RCV000850988	SCV000993222	likely benign	Juvenile myopathy, encephalopathy, lactic acidosis AND stroke	2019-07-12	criteria provided, single submitter	clinical testing	The NC_012920.1:m.10046T>C variant in MT-TG gene is interpreted to be a Likely Benign variant based on the modified ACMG guidelines (unpublished). This variant meets the following evidence codes reported in the guidelines: BP4, BP6
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000223791	SCV000280193	uncertain significance	not specified	2014-12-07	no assertion criteria provided	clinical testing	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. MT-TG m.10046T>C This variant is absent from control individuals to date (see below). This variant has not been reported in association with cardiomyopathy in the scientific literature and available mitochondrial mutation databases. This m.10046T>C variant was reported in 1/2,851 unrelated patients from Baylor’s mtWGS cohort. (Tang et al. 2013) No clinical data is included, and the individual's mother was unavailable for targeted analysis. Note, the majority of the patients included in the Tang et al. 2013 are pediatric cases. The location of the nucleotide change is at the distal end of the T-stem of the mitochondrial tRNA-Gly, and the m.10046 is mostly conserved among species as a Watson-Crick base pair. This variant changes the normal Watson Crick A-T base pair to a C-A mismatch, and this is likely to alter the secondary structure of this tRNA. Mutations affecting tRNA structure have been implicated in cardiomyopathy (Ito et al. 1992; Degoul et al. 1998). Tang et al. 2013 found through analysis of the distribution of the 127 (111 from mtWGS and 16 from mtWGS–NGS) point mutations detected by mtWGS and mtWGS–NGS in mitochondrial protein-coding genes, rRNA genes, and tRNA genes revealed that tRNA genes are indeed the hotspots for mutations (Supp. Table S3; Tang et al. 2013). In total the m.10046T>C variant is absent from 12,830 control individuals from the publicly available and laboratory databases (0 of 2704 control individuals in mtDB; 0 of 3735 individuals in MitoWheel). There is a nearby variant (m.10044A>G) associated with sudden death per an OMIM submission (as of December 7, 2014).