Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV002260594 | SCV002540728 | likely pathogenic | Mitochondrial disease | 2022-06-30 | reviewed by expert panel | curation | The m.11777C>A (p.R340S) variant in MT-ND4 has been reported in at least eight unrelated individuals with primary mitochondrial disease and features including Leigh syndrome, stroke-like episodes, and cardiomyopathy (PS4_moderate; PMIDs: 12707444, 16120329, 15576045, 20502985, 24642831, 29428506). Ages of onset varied from the first few days of life to the 60s and heteroplasmy levels in affected individuals ranged from 50-93%. There is one report of the variant being absent in mother’s blood (PMID: 16120329) however no additional tissues were tested and technology performed at the time of publication would not detect low heteroplasmy levels of the variant. This variant segregated with disease in one family, as two healthy family members had lower to undetectable levels of the variant (PP1; PMID: 20502985). 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 a known pathogenic variant – m.11778G>A (p.R340H, PM5). Cybrid studies supported the functional impact of this variant (PS3_supporting; PMID: 16120329). The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.83 (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 24, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_moderate, PP1, PS3_supporting, PM2_supporting, PM5, PP3. |
| Wong Mito Lab, |
RCV000854746 | SCV000997788 | pathogenic | Leber optic atrophy | 2019-10-17 | criteria provided, single submitter | clinical testing | The NC_012920.1:m.11777C>A (YP_003024035.1:p.Arg340Ser) variant in MTND4 gene is interpretated to be a Pathogenic variant based on the modified ACMG guidelines (unpublished). This variant meets the following evidence codes: PS3, PM8, PM9, PP3, PP4, PP6 |
| OMIM | RCV000010357 | SCV000030583 | pathogenic | Mitochondrial complex I deficiency | 1996-04-01 | no assertion criteria provided | literature only | |
| Gene |
RCV000144013 | SCV000188905 | not provided | Leigh syndrome | no assertion provided | literature only |