To illustrate potential structural consequences of mutations, two examples exhibiting a very high (>80%) variant level and severe alteration of the HRR profile were examined in detail: the variant T11991C, recently also detected in a PCa tissue sample (COSM1132242, [https://cancer.sanger.ac.uk/cosmic/mutation/overview?id=1132242]) leads to substitution of a large hydrophobic, aromatic amino acid by a small, polar amino acid (F411S) interrupting a hydrophobic interaction network based on Pi-stacking between conserved helices in the ND4 domain of CI (Fig. 5c). Here, MT-ND4 is linked to posterior cortical atrophy.