ClinVar Miner

Submissions for variant NC_012920.1(MT-ND3):m.10158T>C

dbSNP: rs199476117
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Total submissions: 6
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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 RCV001796716 SCV002037589 pathogenic Mitochondrial disease 2021-10-26 reviewed by expert panel curation The m.10158T>C (p.S34P) variant in MT-ND3 was reviewed by the Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel as part of the variant pilot for mitochondrial DNA variant specifications (McCormick et al., 2020; PMID: 32906214). This variant has been reported in >16 individuals with primary mitochondrial disease with onset ranging from the first year of life to adulthood and who had features variably consistent with Leigh syndrome, MELAS and MELAS-like, and/or lactic acidosis (PS4; PMID: 14705112; PMID: 14684687; PMID: 27348141; PMID: 28050007; PMID: 27742419; PMID: 28916229; PMID: 14764913; PMID: 22115768; PMID: 15576045; PMID: 30128709; PMID: 29237403; PMID: 31178082; https://doi.org/10.1111/ncn3.17). This variant has been identified as a de novo occurrence in at least seven probands with primary mitochondrial disease (PM6_strong; PMID: 28916229; PMID: 14764913; PMID: 14705112; PMID: 14684687; PMID: 31178082). This variant segregated with disease in multiple members in at least two families (PP1; PMID: 27742419; PMID: 14705112) and one healthy mother was found to have the variant at low heteroplasmy level (PMID: 14705112). This variant is absent from Mitomap's GenBank sequences and gnomAD v3.1.2 (PM2_Supporting). 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). Cybrid studies showed tight correlation between variant heteroplasmy level and complex I activity (PS3_supporting; PMID: 14705112). In summary, this variant meets criteria to be classified as pathogenic for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD U24 Mitochondrial Disease Variant Curation Expert Panel as of August 20, 2020. Mitochondrial DNA-specific ACMG/AMP criteria applied: PS3_supporting, PS4, PM2_supporting, PM6_strong, PP1, PP3).
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics RCV000224598 SCV000281629 pathogenic not provided 2014-08-26 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000224598 SCV000885734 pathogenic not provided 2017-06-16 criteria provided, single submitter clinical testing The m.10158T>C variant (rs199476117) affects the MT-ND3 gene involved in mitochondrial complex I (CI) function, and has been identified in several patients with symptoms of Leigh disease (LD; see link to GeneReviews below). For example, this variant was identified as a presumed de novo variant in the three independent families affected with LD as assessed by McFarland et al (2004). Cells isolated from patients harboring this variant had reduced levels of fully assembled complex I, and cybrid cell lines generated with the m.10158T>C variant had a reduction in complex I activity concomitant with the degree of heteroplasmy in individual established lines (McFarland 2004). Additional LD patients carrying this variant have also been described (Bugiani 2004 and Valente2009), whereas m.10158T>C is absent from the general population (MITOMAP). Therefore, the m.10158T>C variant satisfies our criteria for classification as pathogenic.
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine RCV000144009 SCV000997663 pathogenic Leigh syndrome 2019-10-17 criteria provided, single submitter clinical testing The NC_012920.1:m.10158T>C (YP_003024033.1:p.Ser34Pro) variant in MTND3 gene is interpretated to be a Pathogenic variant based on the modified ACMG guidelines (unpublished). This variant meets the following evidence codes: PS1, PM8, PM9, PM10
OMIM RCV000010360 SCV000030586 pathogenic Mitochondrial complex 1 deficiency, mitochondrial type 1 2004-09-01 no assertion criteria provided literature only
GeneReviews RCV000144009 SCV000188901 not provided Leigh syndrome no assertion provided literature only

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