ClinVar

Description

The c.607C>T (p.R203W) alteration is located in coding exon 4 of the PACS1 gene. This alteration results from a C to T substitution at nucleotide position 607, causing the arginine (R) at amino acid position 203 to be replaced by a tryptophan (W). Based on data from gnomAD, the T allele has an overall frequency of 0.001% (1/152152) total alleles studied. The highest observed frequency was 0.002% (1/41434) of African/African American alleles. This one allele was reported with low allele balance (0.2-0.25). This recurrent de novo alteration has been reported in multiple individuals with Schuurs-Hoeijmakers syndrome, with commonly reported features including developmental delay/intellectual disability, dysmorphic facial features, seizures, and other congenital malformations (Schurrs-Hoeijmakers, 2016; Deciphering Developmental Disorders Study, 2017; Stern, 2017; Gadzicki, 2015; Tenorio-Castaño, 2021). This amino acid position is highly conserved in available vertebrate species. The p.R203W substitution is positioned in the furin (cargo)-binding region of PACS1, which lies directly adjacent to the R196RKRY CK2-binding motif. This motif regulates phosphorylation status of the autoregulatory domain and PACS1 gene activation (Shuurs-Hoeijmakers, 2012). Functional analysis in zebrafish embryos with overexpression of mutant mRNA with this alteration demonstrated a significant reduction in cranial cartilaginous structures at the ventral aspect. In addition, overexpression of this altered protein resulted in defective migration of cranial-neural-crest cells in the head. Studies in human embryonic kidney cells demonstrated that expression of mutant PACS1 remains more stable than the wild-type protein leading to observed cellular aggregates (Shuurs-Hoeijmakers, 2012). The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic.