Sarah Leigh changed review comment from: Comment on mode of inheritance: PMID 29079705 reports a novel de novo dominant variant in ISCU associated with mitochondrial myopathy, which justifies the mode of inheritance recorded.; to: Comment on mode of inheritance: PMID 29079705 reports a novel de novo dominant variant missense p.G97V variant has been reported and therefore this may represent a specific mechanism of action. Further evidence is needed to determine which (if any) other monoallelic variants will cause disease beyond mitochondrial myopathy, which justifies the mode of inheritance recorded.
Sarah Leigh Added comment: Comment on mode of inheritance: PMID 29079705 reports a novel de novo dominant variant in ISCU associated with mitochondrial myopathy, which justifies the mode of inheritance recorded.
Sarah Leigh Mode of inheritance for gene: ISCU was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Sarah Leigh Added comment: Comment on list classification: This gene was discussed on the NHSE GMS Mitochondrial Specialist Group Meeting call on 25th February 2019. It was confirmed that Perrault syndrome was relevant for this panel, and that there was enough evidence for the gene to be Green.
Sarah Leigh Added comment: Comment on list classification: Sufficient published reported biallelic cases, with supportive functional studies. The most frequent reported variant c.343+382G>C g.108567650G>C is deep in intron five of the gene and strengthens a weak splicing acceptor site, with consequent retention of a 100-bp intronic sequence upstream of the known terminal exon, introduction of a stop codon and decreased levels of ISCU mRNA and protein (PMID 18304497). This may be missed by standard sequencing.