Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Clin |
RCV002260583 | SCV002540731 | uncertain significance | Mitochondrial disease | 2022-06-30 | reviewed by expert panel | curation | The m.1606G>A variant in MT-TV has been reported in two affected individuals in two families (PMIDs: 9450773, 2056939), however haplogroups were not provided as necessary to apply PS4_supporting. These two individuals had strikingly similar courses, as both were males who were relatively healthy until their 20s/30s when they developed progressive cognitive impairment. Other features seen in both men include bilateral cataracts, bilateral SNHL, imbalance/ataxia, and basal ganglia classifications, with both men harboring the variant at 67-70% heteroplasmy. This variant occurred de novo in one individual (absent in blood and urine from mother and brother; PM6_supporting, PMID: 12056939). There is one report of this variant segregating with disease features as a healthy mother of a proband had the variant present at <10% in muscle, however this does not meet criteria to apply PP1_supporting (at least two segregations). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). Single fiber testing showed higher levels of the variant in COX negative fibers (85%) than in COX positive fibers (57%), p<0.0001 (PS3_supporting, PMID: 9450773). The computational predictor MitoTIP suggests this variant impacts the function of this tRNA with a score of 73.6%, as does HmtVar with a score of 0.9 (PP3). In summary, this variant meets criteria to be classified as uncertain significance 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 27, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM6_supporting, PS3_supporting, PM2_supporting, PP3. |
Wong Mito Lab, |
RCV000850660 | SCV000992891 | pathogenic | MELAS syndrome | 2019-07-12 | criteria provided, single submitter | clinical testing | The NC_012920.1:m.1606G>A variant in MT-TV gene is interpreted to be a Pathogenic variant based on the modified ACMG guidelines (unpublished). This variant meets the following evidence codes reported in the guidelines: PS3, PS5, PM7 |
OMIM | RCV000010156 | SCV000030377 | pathogenic | Ataxia, progressive seizures, mental deterioration, and hearing loss | 2002-06-01 | no assertion criteria provided | literature only |