Submissions for variant NM_000277.3(PAH):c.890G>T (p.Arg297Leu)

dbSNP: rs62642939

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000993640	SCV001146772	likely pathogenic	Phenylketonuria	2019-07-07	reviewed by expert panel	curation	The c.890G>T (p.Arg297Leu) variant in PAH has been reported in at least 1 patient with mild PKU who carried in trans the nonsense variant R243X (BH4 deficiency was not excluded) (PMID: 17096675). This variant is absent from the gnomAD and ESP population databases. Biochemical assays demonstrate a loss of ~50% enzyme activity (PMID: 18346471 & 21820508). Other amino acid changes at this codon have been reported. Overall, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3, PS3.
Invitae	RCV000993640	SCV002271532	likely pathogenic	Phenylketonuria	2021-04-30	criteria provided, single submitter	clinical testing	Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PAH protein function. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Arg297 amino acid residue in PAH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8807331, 27121329, 23357515, 10234516, 21307867, 9298832, 25596310). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. This variant has been observed in individual(s) with hyperphenylalaninemia (PMID: 17096675). ClinVar contains an entry for this variant (Variation ID: 805823). This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with leucine at codon 297 of the PAH protein (p.Arg297Leu). The arginine residue is weakly conserved and there is a moderate physicochemical difference between arginine and leucine.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000993640	SCV004240806	likely pathogenic	Phenylketonuria	2023-12-11	criteria provided, single submitter	clinical testing	Variant summary: PAH c.890G>T (p.Arg297Leu) results in a non-conservative amino acid change located in the Aromatic amino acid hydroxylase, C-terminal domain (IPR019774) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251036 control chromosomes (gnomAD). c.890G>T has been reported in the literature in at least one individual affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (Daniele_2006). In addition, other amino acid changes (R297H, R297C) at this codon have been found in patients with Phenylketonuria (Hillert_2020). These data indicate that the variant is likely to be associated with disease. Functional studies reported experimental evidence evaluating an impact on protein function and this variant effect results in 30%-50% of normal activity (Daniele_2008, Cerreto_2011). The following publications have been ascertained in the context of this evaluation (PMID: 21820508, 17096675, 18346471, 30275481, 32668217). Two submitters, including one expert panel (ClinGen PAH Variant Curation Expert Panel), have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.