Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV003319214 | SCV004023272 | likely benign | Mitochondrial disease | 2023-07-10 | reviewed by expert panel | curation | The m.6951G>A variant in MT-CO1 was reviewed by the Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel on July 10, 2023. There are no individuals or families with primary mitochondrial disease with this variant reported in the medical literature to our knowledge. Multiple unaffected family members were found to be homoplasmic for this variant in private databases known to this expert panel. In all of these families, the affected individuals had alternate genetic causes determined for their disease (BP5). This variant is present at low frequency in population databases. The frequency in gnomAD v3.1.2 is 26/56,416 (0.046%) with 26 homoplasmic occurrences and one heteroplasmic occurrence spread over eight top level haplogroups (single letter) with European, Asian, and African ancestry. The frequency in MITOMAP GenBank sequences is 20/59,389 (0.034%) spread over eight top level haplogroups with European, and Asian ancestry. The frequency in the Helix dataset is 75/195,983 (0.038%, all homoplasmic) plus an additional 13 heteroplasmic occurrences, all spread over 17 top level haplogroups with European, Asian, and African ancestry. Therefore, the frequency of this variant meets neither criteria for pathogenicity (<0.002%) nor benign status (>0.5%). The computational predictor APOGEE gives scores of 0.41 (“neutral”) in APOGEE1 and 0.101 (“likely benign”) in APOGEE2 (Min=0, Max=1), which predict a no impact on gene function (BP4). There are no cybrids, single fiber studies, or other functional assays reported on this variant to date. In summary, this variant meets criteria to be classified as likely benign for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on July 10, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied: BP4, BP5. |
| Wong Mito Lab, |
RCV000854011 | SCV000997044 | likely benign | Leigh syndrome | 2019-10-17 | criteria provided, single submitter | clinical testing | The NC_012920.1:m.6951G>A (YP_003024028.1:p.Val350Met) variant in MTCO1 gene is interpretated to be a Likely Benign variant based on the modified ACMG guidelines (unpublished). This variant meets the following evidence codes: BS1, BP4 |
| Athena Diagnostics | RCV000992345 | SCV001144566 | uncertain significance | not provided | 2018-12-10 | criteria provided, single submitter | clinical testing |