Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV001260444 | SCV001437441 | likely pathogenic | Mitochondrial complex 5 (ATP synthase) deficiency, nuclear type 6 | 2020-09-22 | criteria provided, single submitter | clinical testing | Variant summary: USMG5 (also known as ATP5MD) c.87+2dupT alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: 4/4 predict that the variant abolishes a 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.2e-05 in 240220 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.87+2dupT in individuals affected with Mitochondrial Complex 5 (ATP Synthase) Deficiency, Nuclear Type 6 (MC5DN6) and no experimental evidence demonstrating its impact on protein function have been reported. However, a different variant that affects the same splice site, c.87+1G>C, has been reported as a homozygous mutation in at least 4 Ashkenazi Jewish individuals affected with Leigh syndrome, and functional studies demonstrated that this variant resulted in the lack of the protein product, which caused impairment in mitochondrial ATP production (PMID: 29917077). These findings suggest that the current variant might have similar effects. No clinical diagnostic laboratories have submitted clinical-significance assessments for the current variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic. |