Total submissions: 7
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV002260592 | SCV002540735 | likely pathogenic | Mitochondrial disease | 2022-06-30 | reviewed by expert panel | curation | The m.13042G>A (p.A236T) variant in MT-ND5 has been reported in six unrelated individuals with primary mitochondrial disease with onset ranging from the first year of life to adulthood; and features variably consistent CPEO, LHON, MERRF/MELAS, Leigh-like syndrome (PS4_moderate; PMIDs: 15767514; 17400793; 31996177; 16816025). This variant segregated with disease in a family with LHON as the proband's heteroplasmy was 41% in urine and his affected sister had the variant present at 39% in urine and 91% in muscle. There were unaffected sisters (heteroplasmy levels of 4% and 20% in urine) as well as an unaffected brother with the variant present at 43% urine. In another family, this variant segregated with Leigh syndrome in the proband (heteroplasmy level in in blood was 77%, in muscle was 84%, in fibroblasts was 86%); the healthy mother harbored the variant in hair (25%) and blood (11%); and the proband’s maternal grandmother was found to have the variant at < 2% in blood and between 4-6% in muscle (PP1_moderate, PMIDs: 16816025 17400793). There are no reports of confirmed de novo occurrences to our knowledge. This variant is absent in the Helix dataset and gnomAD v3.1.2, and there is only one occurrence in the GenBank dataset (PM2_supporting). The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.85 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). There are no cybrids, single fiber studies, or other functional assays reported on this variant. 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 13, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_moderate, PP1_moderate, PP3, PM2_supporting. |
| Wong Mito Lab, |
RCV000854885 | SCV000997930 | pathogenic | Leber optic atrophy | 2019-10-17 | criteria provided, single submitter | clinical testing | The NC_012920.1:m.13042G>A (YP_003024036.1:p.Ala236Thr) 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, PM8, PM9, PM10 |
| 3billion, |
RCV000010347 | SCV004013770 | likely pathogenic | MELAS syndrome | criteria provided, single submitter | clinical testing | The variant is not observed in the gnomAD v2.1.1 dataset. Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000009703). Should be validated by an alternate clinical test Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. | |
| OMIM | RCV000010347 | SCV000030573 | pathogenic | MELAS syndrome | 2007-04-01 | no assertion criteria provided | literature only | |
| OMIM | RCV000010348 | SCV000030574 | pathogenic | MERRF syndrome | 2007-04-01 | no assertion criteria provided | literature only | |
| OMIM | RCV000010349 | SCV000030575 | pathogenic | Leigh syndrome due to mitochondrial complex I deficiency | 2007-04-01 | no assertion criteria provided | literature only | |
| Gene |
RCV000010347 | SCV004042637 | not provided | MELAS syndrome | no assertion provided | literature only |