Submissions for variant NC_012920.1:m.13094T>C

dbSNP: rs1603224029

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen	RCV002291219	SCV002583526	pathogenic	Mitochondrial disease	2022-07-25	reviewed by expert panel	curation	The m.13094T>C (p.V253A) variant in MT-ND5 has been reported in at least 25 individuals with primary mitochondrial disease from 18 families. Affected individuals had variable ages of onset (first months of life to childhood to 20s). Features included Leigh syndrome, MELAS, and LHON. Heteroplasmy levels were variable among tissues and affected individuals, however there are no reports of the variant being homoplasmic to our knowledge (PS4; PMIDs: 29506874, 29479304, 28429146, 23918514, 22577219, 20818383, 18977334; https://www.chop.edu/stories/melas-syndrome-ginas-and-her-familys-story). This variant segregated with disease in multiple families as healthy family members had lower to undetectable levels of the variant (PP1_moderate; PMIDs: 29506874, 29479304). This variant occurred de novo in at least two individuals (PM6_supporting, PMIDs: 23918514, 18977334). This variant is absent in population databases after removing sequences from individuals with mitochondrial disease (one occurrence in GenBank sequences is from an individual with mitochondrial disease; absent in gnomAD v3.1.2 and Helix dataset; PM2_supporting). Cybrid studies show two different classes of function defects (PS3_moderate): (1) complex I/CS activity ratio is highly correlated with the percentage of the variant and loss of ND5 is associated with instability of the membrane arm of Complex I (PMID: 18977334) and (2) autophagy, determined as LC3B-II/Actin levels, was significantly increased in mutant cybrids (PMID: 29479304). The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.89 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). In summary, this variant meets criteria to be classified as pathogenic for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 Mitochondrial Disease Variant Curation Expert Panel on July 25, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM2_supporting, PP3, PP1_moderate, PS3_moderate, PM6_supporting, PS4.
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	RCV000854891	SCV000997936	pathogenic	Juvenile myopathy, encephalopathy, lactic acidosis AND stroke	2019-10-17	criteria provided, single submitter	clinical testing	The NC_012920.1:m.13094T>C (YP_003024036.1:p.Val253Ala) variant in MTND5 gene is interpretated to be a Pathogenic variant based on the modified ACMG guidelines (unpublished). This variant meets the following evidence codes: PS3, PM8, PM9, PP4, PP6
Mendelics	RCV002249552	SCV002517678	pathogenic	Leber optic atrophy	2022-05-04	criteria provided, single submitter	clinical testing
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV000854891	SCV004012093	pathogenic	Juvenile myopathy, encephalopathy, lactic acidosis AND stroke	2022-03-17	criteria provided, single submitter	research