ClinVar

This variant is classified as a variant of unknown significance because its contribution to a variable phenotype including muscle weakness, neurologic abnormalities, and increased blood lactate has not been confirmed.

In 8 individuals (3 females and 5 males) across 3 generations of a family with variable clinical features including muscle weakness, neurologic abnormalities, and increased blood lactate, Beninca et al. (2021) identified hemizygosity in the males and heterozygosity in the females for a c.350T-C transition in exon 5 of the APOO gene, resulting in an ile117-to-thr (I117T) substitution. The mutation was found by whole-exome sequencing in the 8-year-old proband and by Sanger sequencing in the other affected individuals. Three clinically unaffected females in the family were also heterozygous for the variant. X-chromosome skewing patterns were inconclusive in some affected females and were shown to be skewed in others. The variant was not found in the ExAC or 1000 Genomes Project databases. Abnormal processing of the 22-kD isoform of APOO was demonstrated in fibroblasts from one of the patients. Patient fibroblasts also showed abnormal MICOS complex assembly and abnormal christae junctions. Studies in HeLa cells suggested that APOO with the I117T mutation has a looser association with the mitochondrial inner membrane compared to wildtype.