ClinVar

Description

The P953R variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. Adequate data is not available in large population cohorts to assess the frequency of this variant in publicly available databases (Lek et al., 2016); however, this variant has not been detected in presumably healthy individuals tested at GeneDx. The P953R variant is a non-conservative amino acid substitution that occurs at a position that is conserved in mammals. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Although the variant occurred de novo in a patient tested at GeneDx, the majority of pathogenic variants reported in SHANK3 are loss-of-function, and the clinical significance of most missense variants is not well established (Stenson et al., 2014). Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.