Submissions for variant NC_012920.1(MT-TW):m.5536_5537insT

dbSNP: rs1603220010

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	RCV004595536	SCV005088557	likely pathogenic	Mitochondrial disease	2023-05-23	reviewed by expert panel	curation	The m.5537insT variant in MT-TW has been reported in seven affected individuals from two families (PS4_supporting; PMIDs: 9266739, 12776230). Ages of onset included infancy, childhood, adolescence, and adulthood. Features in affected individuals included Leigh syndrome spectrum disorder, optic atrophy, migraine, gastrointestinal dysmotility, and mood disorders. Muscle biopsies showed ragged red fibers, subsarcolemmal accumulation of mitochondria, COX-negative fibers, and complex IV deficiency (and to a lesser extent, complex I deficiency). Heteroplasmy levels were >95% in the two individuals with Leigh syndrome, and were variable in the other affected family members. The variant segregated with clinical manifestations in both reported families (PP1_moderate; PMIDs: 9266739, 12776230). The variant segregated in the first reported family (PMID: 9266739) as the severely affected male proband with Leigh syndrome had the variant at >95% heteroplasmy; his generally healthy sister with optic nerve pallor and incoordination had the variant at 89%; his mother with thin habitus, depression, irritable bowel, and migraines had the variant present at 75%; and his maternal grandmother maternal aunt with depression had the variant present at 42% and 78% respectively). Furthermore, the variant was present at a lower heteroplasmy level in the healthy mother of the second case (PMID: 12776230). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). While there are no in silico predictors for this variant type, an insertion at this location in the tRNA is highly likely to disrupt its structure, and other variants at this position are predicted to be deleterious (PP3). Single fiber testing showed higher levels of the variant in abnormally appearing muscle fibers (such as ragged red fibers, 97% +/- 2%) than in normal appearing fibers (90% +/- 6%), p<0.0005 (PS3_supporting; PMID: 9266739). 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 May 23, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_supporting, PP1_moderate, PM2_supporting, PP3, PS3_supporting.
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	RCV000850782	SCV000993015	pathogenic	Juvenile myopathy, encephalopathy, lactic acidosis AND stroke	2019-07-12	criteria provided, single submitter	clinical testing	The NC_012920.1:m.5536_5537insT variant in MT-TW 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, PM9, PM10, PP4, PP6