ClinVar

Description

Variant summary: PAH c.30C>G alters a non-conserved nucleotide resulting in a synonymous change. 4/4 computational tools predict no significant impact on normal splicing. This variant was shown to cause aberrant mRNA splicing in two different reporter minigenes (example, Dobrowolski_2010), however the exact implications of this in-vitro finding on in-vivo impact of this variant is not clear. The variant allele was found at a frequency of 0.00064 in 251468 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in PAH causing Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (0.00064 vs 0.0079), allowing no conclusion about variant significance. c.30C>G was initially described in a family with three siblings who presented with different clinical manifestations of Hyperphenylalaninemia ranging from "normal" (Sibling A) to severe retardation (Sibling B) and dietarily responsive (Sibling C) (DiSilvestre_1991). As this study predated PAH gene sequencing, the exact variation was not specified. In a subsequent report, two of these three siblings were reported as harboring this variant but their exact identity relative to the previously published report was not specified (example, Dobrowolski_2010). These report(s) do not provide unequivocal conclusions about association of the variant with Phenylalanine Hydroxylase Deficiency (Phenylketonuria). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.