ClinVar

Description

Across a selection of available literature, the PACS1 c.607C>T (p.Arg203Trp) missense variant has been found in a heterozygous state in at least 35 individuals with PACS1-related Syndrome (Schuurs-Hoeijmakers et al. 2012; Farwell et al. 2015; Schuurs-Hoeijmakers et al. 2016, Lazaridis et al. 2016; Stern et al. 2017; Tarailo-Graovac et al. 2017; Bowling et al. 2017; Geisheker et al. 2017; Pefkianaki et al. 2018; Dutta et al. 2019). This variant was identified as de novo in the affected individuals in all instances where parental samples were available. Control data are unavailable for this variant, which is absent from the Genome Aggregation Database in an area of good sequencing coverage, so the variant is presumed to be rare. Expression of the variant PACS1 mRNA in zebrafish embryos induced craniofacial defects (Schuurs-Hoeijmakers et al. 2012). The authors also showed that the p.Arg203Trp variant results in the formation of cytoplasmic aggregates and altered protein trafficking, and suggested a dominant-negative affect on the protein. Based on the collective evidence, the p.Arg203Trp variant is classified as pathogenic for PACS1-related syndrome.