ClinVar Miner

Submissions for variant NC_012920.1(MT-ND6):m.14513_14514del

dbSNP: rs1603224770
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Total submissions: 2
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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 RCV000984482 SCV004801747 likely pathogenic Mitochondrial disease 2023-12-21 reviewed by expert panel curation The m.14513_14514delAT (p.Met54SerfsTer7) variant in MT-ND6 has been reported in one individual to date, in a man with mitochondrial myopathy characterized by adolescent onset exercise intolerance and muscle weakness as well as ptosis, reduced muscle bulk, and lumbar lordosis. Muscle biopsy showed that 13% of muscle fibers were ragged red fibers (RRF) and >75% of fibers showed a complete loss of NDUFB8 immunoreactivity associated with preserved COX-I immunoreactivity (PMID: 32158465). The variant was present at 76% heteroplasmy in skeletal muscle, 10% in urine, and was undetectable in blood and buccal samples. As this is the only case reported to date, PS4 could not be applied. The variant was absent in blood, buccal, and urine samples from his healthy mother (PM6_supporting). Computational predictors are not applicable for this variant type precluding consideration for PP3 or BP4. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). This variant results in a frame shift at position 54 and is predicted to result in loss of >10% protein (PVS1_strong). Single fiber testing showed that heteroplasmy levels in COX-positive ragged-red fibers was 90.9 ± 0.74% (n=21) and in COX-positive non-ragged-red fibers was 31.7 ± 9.6% (n=17; p < 0.0001; PS3_supporting; PMID: 32158465). 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 ClinGen Mitochondrial Disease Variant Curation Expert Panel on December 21, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM6_supporting, PM2_supporting, PS3_supporting, PVS1_strong.
Wellcome Centre for Mitochondrial Research, Newcastle University RCV000984482 SCV001132040 pathogenic Mitochondrial disease 2019-12-09 criteria provided, single submitter clinical testing

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