ClinVar Miner

Submissions for variant m.10191T>C

dbSNP: rs267606890
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Total submissions: 5
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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 RCV002291212 SCV002583521 pathogenic Mitochondrial disease 2022-08-23 reviewed by expert panel curation The m.10191T>C (p.S45P) variant in MT-ND3 has been reported in at least 30 unrelated individuals with primary mitochondrial disease. Of note, to our knowledge, all reported individuals have been the only affected person in the family. Affected individuals had variable ages of onset (birth to 20s) and outcomes (death in first month of life to alive in 20s at the time of report). Features included Leigh syndrome, MELAS-like syndrome, and Leigh/MELAS overlap, as well as epilepsia partialis continua (EPC) and optic atrophy. Heteroplasmy levels ranged from 13%-100% in affected individuals (PS4; PMIDs: 11456298, 14684687, 15576045, 14705112, 16044424, 16023078, 17535832, 18078792, 19135620, 19617458, 19520270, 20691940, 20226758, 20972245, 22364517, 28429146, 27450679, 30128709, 31261379). There is one report of this variant segregating with disease features as a healthy mother of a proband had the variant present at 3% in blood (PMID: 11456298), however this does not meet criteria to apply PP1_supporting (at least two segregations). This variant was seen in the mother’s blood in two other families (36% heteroplasmy in PMID: 16044424; 5% in mother’s blood and undetectable in maternal grandmother’s blood in PMID: 16023078), however no clinical details were provided on these family members to know if they were healthy or affected. There are at least six reports of de novo occurrences of this variant (PM6_strong; PMIDs: 14705112, 18078792, 19520270, 22364517, 27450679). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). Cybrid studies supported the functional impact of this variant (PS3_supporting; PMID: 14705112). 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 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 August 23, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM2_supporting, PP3, PS3_supporting, PM6_strong, PS4.
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine RCV000144010 SCV000997666 pathogenic Leigh syndrome 2019-10-17 criteria provided, single submitter clinical testing The NC_012920.1:m.10191T>C (YP_003024033.1:p.Ser45Pro) 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, PM9, PM10, PP4, PP6
OMIM RCV000010358 SCV000030584 pathogenic Mitochondrial complex 1 deficiency, mitochondrial type 1 2004-01-01 no assertion criteria provided literature only
GeneReviews RCV000144010 SCV000188902 not provided Leigh syndrome no assertion provided literature only
Genomics England Pilot Project, Genomics England RCV001542636 SCV001760531 likely pathogenic Mitochondrial complex I deficiency no assertion criteria provided clinical testing

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