Submissions for variant NC_012920.1(MT-TQ):m.4332G>A

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Total submissions: 3

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen	RCV003162235	SCV003915450	uncertain significance	Mitochondrial disease	2023-01-23	reviewed by expert panel	curation	The m.4332G>A variant in MT-TQ has been reported in one individual from one family to date (PMID: 11171912), in a man with an atypical presentation of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS). This individual had hearing loss beginning in his 20s and a stroke-like episode in his 40s. Muscle biopsy showed ragged red fibers and COX-deficient fibers, along with decreased activity of respiratory chain complex IV. The variant was present at 81% in muscle and undetectable in fibroblasts and skin. While the variant was absent in blood from his mother and brother, it was also undetectable in the proband’s blood, therefore it is unclear if this was a de novo variant. There are no large families reported in the medical literature to consider for evidence of segregation. Of note, there is another individual reported with MELAS and this variant, however insufficient clinical details were provided to include this case for consideration for this variant curation (PMID: 20064630). The computational predictor MitoTIP suggests this variant impacts the function of this tRNA (81st percentile) as does HmtVar with a score of 0.7 (PP3). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). Single fiber testing showed higher levels of heteroplasmy in COX-negative fibers (mean 99.3% and ranging from 98.8-99.7%, n=13) than in COX-positive fibers (mean 70.5% and ranging from 46.5-94.5%, n=11; p=0.002; PMID: 11335700; PS3_supporting). In summary, this variant meets criteria to be classified as uncertain significance 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 January 23, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM2_supporting, PP3, PS3_supporting.
OMIM	RCV000010240	SCV000030464	pathogenic	MELAS syndrome	2001-02-13	no assertion criteria provided	literature only
GeneReviews	RCV000010240	SCV004042619	not provided	MELAS syndrome		no assertion provided	literature only

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