ClinVar

Description

Variant summary: PKHD1 c.667G>A (p.Gly223Ser) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant also alters the last conserved nucleotide of exon 9 adjacent to the intron 9 splice donor site. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 2e-05 in 250824 control chromosomes. c.667G>A has been reported in the literature in multiple individuals from a consanguineous multiplex Pakistani family affected with Polycystic Kidney And Hepatic Disease (example, Bergmann_2003) and in at-least one Italian individual with this condition in whom a second variant was not identified following comprehensive genotyping for the PKHD1 gene (example, Melchionda_2016). These data indicate that the variant is likely to be associated with disease. However, the authors of the primary report do speculate that a non-causative outcome for this variant cannot be entirely ruled out (Bergmann_2003). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance citing an overlapping evidence utilized in the context of this analysis. Based on the evidence outlined above, until additional clinical segregation and/or functional evidence is identified, the variant was classified as VUS-possibly pathogenic.