Submissions for variant NC_012920.1:m.13514A>G

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Total submissions: 4

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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	RCV002260618	SCV002540726	likely pathogenic	Mitochondrial disease	2022-06-30	reviewed by expert panel	curation	The m.13514A>G (p.D393G) variant in MT-ND5 has been reported in at least 12 unrelated individuals with primary mitochondrial disease with onset ranging from childhood to adulthood and features variably consistent with Leigh syndrome and MELAS, as well as hypertrophic cardiomyopathy, optic atrophy, and neuropathy (PS4_moderate; PMIDs: 26341968, 25974876, 32504279, 20972245, 23847141, 21712854, 15576045, 14684687, 11198278). Heteroplasmy levels in affected individuals ranged from 55-70% in muscle, 12-55% in fibroblasts, 4-50% in blood, and 90% heart. This variant has been identified as a de novo occurrence in at least two probands with primary mitochondrial disease (PM6_supporting; PMIDs: 14684687, 11198278). 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). Another variant at this amino acid position leading to a different amino acid change is classified as pathogenic by this Expert Panel – m.13513G>A (p. D393N, PM5). Cybrid studies showed a tight correlation between higher heteroplasmy level and lower complex I activity (PS3_supporting, PMID: 11198278). The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.95 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). 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 Mitochondrial Disease Variant Curation Expert Panel on May 3, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_moderate, PM6_supporting, PM2_supporting, PM5, PS3_supporting, PP3.
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	RCV000144017	SCV000997987	pathogenic	Leigh syndrome	2019-10-17	criteria provided, single submitter	clinical testing	The NC_012920.1:m.13514A>G (YP_003024036.1:p.Asp393Gly) 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: PS1, PS3
GeneReviews	RCV000144017	SCV000188909	not provided	Leigh syndrome		no assertion provided	literature only
GeneReviews	RCV003333959	SCV004042639	not provided	Juvenile myopathy, encephalopathy, lactic acidosis AND stroke		no assertion provided	literature only

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