Submissions for variant m.14453G>A

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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	RCV002260589	SCV002540730	likely pathogenic	Mitochondrial disease	2022-06-30	reviewed by expert panel	curation	The m.14453G>A (p.A74V) variant in MT-ND6 has been reported in at least 10 individuals with primary mitochondrial disease from 10 families. Affected individuals had onset ranging from the first day of life to adulthood (all but one case had early childhood onset, however); and with features variably consistent with Leigh syndrome and MELAS (PS4_moderate; PMIDs: 34933128, 22947169, 33644659, 32552696, 24642831, 21364701, 11781695). Heteroplasmy levels ranged from 41-83%. There are at least five reports of de novo occurrences of this variant (PM6_strong, score 2.5; PMIDs: 34933128, 33644659, 24642831, 11781695). There is one report of this variant segregating with disease features as a healthy mother of a proband had the variant present at 2% in blood, however this does not meet criteria to apply PP1_supporting (at least two segregations). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). There are no cybrid studies, single fiber studies, or other functional assays reported for this variant. The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.81 (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 June 27, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_moderate, PM6_strong, PM2_supporting, PP3.
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	RCV000855109	SCV000998156	likely pathogenic	Leigh syndrome	2019-10-17	criteria provided, single submitter	clinical testing	The NC_012920.1:m.14453G>A (YP_003024037.1:p.Ala74Val) variant in MTND6 gene is interpretated to be a Likely Pathogenic variant based on the modified ACMG guidelines (unpublished). This variant meets the following evidence codes: PM9, PM10, PP4, PP6, PP7
OMIM	RCV000010331	SCV000030557	pathogenic	Juvenile myopathy, encephalopathy, lactic acidosis AND stroke	2001-10-01	no assertion criteria provided	literature only
GeneReviews	RCV000010331	SCV004042642	not provided	Juvenile myopathy, encephalopathy, lactic acidosis AND stroke		no assertion provided	literature only

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