Submissions for variant NC_012920.1(MT-TW):m.5521G>A

dbSNP: rs199474673

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen	RCV002291209	SCV002583523	likely pathogenic	Mitochondrial disease	2022-10-03	reviewed by expert panel	curation	The m.5521G>A variant in MT-TW has been reported in four unrelated individuals to date. Ages of onset included childhood (2/4 affected individuals), 20s (1/4 affected individuals), and 50s (1/4 affected individuals). Affected individuals had features including myopathy, seizures, cerebellar ataxia, mood disorders, and eating disorders. Muscle biopsies showed ragged red fibers (RRF) and COX-negative fibers, whereas respiratory chain enzyme deficiencies were variable. Heteroplasmy levels of the variant were not specified in one affected individual, were 98% muscle and undetectable in blood in another affected individual, were homoplasmic in muscle and 87% brain in another affected individual, and were homoplasmic in blood in the last individual (PS4_moderate; PMIDs: 20360171, 23841600, 23847141, 9673981). There are no de novo occurrences of this variant to our knowledge. There are no large families reported in the medical literature to consider for evidence of segregation. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). The computational predictor MitoTIP suggests this variant is pathogenic (89.7 percentile) and HmtVAR predicts it to be pathogenic score of 1 (PP3). Single fiber testing showed higher levels of the variant in COX-negative RRF (89.9% +/- 11.76) than in COX-positive fibers (69.35% +/- 26.22), p<0.005 (PS3_supporting, PMID: 9673981). 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 October 3, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied: PS4_moderate, PM2_supporting, PP3, PS3_supporting.
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	RCV000850777	SCV000993010	pathogenic	Juvenile myopathy, encephalopathy, lactic acidosis AND stroke	2019-07-12	criteria provided, single submitter	clinical testing	The NC_012920.1:m.5521G>A 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, PM7, PM8, PM9, PP6
Mendelics	RCV000850777	SCV002517738	pathogenic	Juvenile myopathy, encephalopathy, lactic acidosis AND stroke	2022-05-04	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV002291209	SCV004101318	likely pathogenic	Mitochondrial disease	2023-07-31	criteria provided, single submitter	clinical testing	The MT-TW m.5521G>A mitochondrial variant has been reported in at least five individuals with phenotypes consistent with primary mitochondrial disease including myopathy, seizures, cerebellar ataxia, mood disorders, and eating disorders (PMID: 23841600; 20360171; 9673981; 37038312; 23847141). The age of onset of disease in the affected individuals ranged between infancy and adult. In at least three of the affected individuals higher heteroplasmy levels of the variant were present in the affected tissue compared to an unaffected tissue (PMID: 9673981; 20360171; 37038312). Single fiber studies performed in muscle tissue from an adult male with progressive bilateral ptosis without ophthalmoplegia, dysphonia and mild proximal muscle wasting and weakness, showed significantly higher levels of the variant in COX-negative ragged red fibers (89.9% +/- 11.76) than in COX-positive fibers (69.35% +/- 26.22), p<0.005 (PMID: 9673981). The m.5521G>A variant is not observed in version 3.1.2 of the Genome Aggregation Database. Multiple lines of computational evidence suggest the variant may impact tRNA structure and stability. This variant has been classified as likely pathogenic by ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel. Based on the available evidence the MT-TW m.5521G>A variant is classified as likely pathogenic for primary mitochondrial disease.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000850777	SCV004242442	likely pathogenic	Juvenile myopathy, encephalopathy, lactic acidosis AND stroke	2023-12-04	criteria provided, single submitter	clinical testing	Criteria applied: PS4_MOD,PS3_SUP,PM2_SUP,PP3,PP4
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV004696632	SCV005196605	pathogenic	not provided	2023-12-22	criteria provided, single submitter	clinical testing
OMIM	RCV000010166	SCV000030387	pathogenic	Inborn mitochondrial myopathy	1998-06-01	no assertion criteria provided	literature only
GeneReviews	RCV000850777	SCV004042620	not provided	Juvenile myopathy, encephalopathy, lactic acidosis AND stroke		no assertion provided	literature only