ClinVar

In 2 sibs (patients 1A and 1B) with mitochondrial complex I deficiency nuclear type 21 (MC1DN21; 618242), Kimonis et al. (2021) identified compound heterozygosity for 2 mutations in the NUBPL gene: a c.815-27T-C transition (c.815-27T-C, NM_025152.3) in intron 9, predicted to cause splicing abnormalities, and a c.311T-C transition, resulting in a leu104-to-pro (L104P; 613621.0009) substitution. The mutations were identified by whole-exome sequencing, and the parents were shown to be mutation carriers. The L104P was reported in the gnomAD database at an allele frequency of 0.00023, and the c.815-27T-C mutation was reported in the gnomAD database at an allele frequency of 0.004476. The allele with the c.815-27T-C mutation was shown not to have the G56R mutation in cis (see 613621.0001), as had been seen in prior patients with the c.815-27T-C mutation. Splicing analysis in whole blood from the sibs showed that the c.815-27T-C mutation resulted in abnormal transcripts, with the 2 most abundant abnormal transcripts containing partial inclusion of intron 9 or skipping of exon 10. Expression of NUBPL with the L104P mutation in yeast showed that it resulted in decreased complex I levels compared to controls.