Submissions for variant NM_000277.3(PAH):c.439C>T (p.Pro147Ser)

dbSNP: rs199475624

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000674963	SCV001448616	likely pathogenic	Phenylketonuria	2020-10-15	reviewed by expert panel	curation	This c.439C>T (p.Pro147Ser) variant in PAH was reported in at least 5 patients with PAH deficiency, detected with pathogenic variants p.Arg243Gln (PMID: 27121329), p.S349P (PMID: 15589814), c.1045T>C, c.782G>A (PMID: 24941924) and p.A403V (PMID: 10234516). DHPR activity, biopterin and/or pteridine analysis was performed to rule out other causes of hyperphenylalaninemia (PMID: 27121329). This variant is present at an extremely low frequency in gnomAD (MAF=0.00003). Computational evidence for this missense variant supports a deleterious effect. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_strong, PM2, PP4_moderate, PP3.
Counsyl	RCV000674963	SCV000800381	likely pathogenic	Phenylketonuria	2018-06-01	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000088917	SCV002046537	likely pathogenic	not provided	2020-12-30	criteria provided, single submitter	clinical testing	The variant has been reported in several symptomatic phenylketonuria patients in literature (PMIDs: 8981952 (1997), 10234516 (1999), 15589814 (2004), 24941924 (2015), and 27121329 (2016)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is disease causing and damaging. Based on the available information, the variant is predicted to be likely pathogenic.
Invitae	RCV000674963	SCV002240784	pathogenic	Phenylketonuria	2023-10-15	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 147 of the PAH protein (p.Pro147Ser). This variant is present in population databases (rs199475624, gnomAD 0.003%). This missense change has been observed in individual(s) with PAH-related conditions (PMID: 10598814, 27121329). ClinVar contains an entry for this variant (Variation ID: 102669). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. This variant disrupts the p.Pro147 amino acid residue in PAH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 26322415, 27121329, 31355225). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000674963	SCV002797087	pathogenic	Phenylketonuria	2022-02-16	criteria provided, single submitter	clinical testing
3billion	RCV000674963	SCV003841532	pathogenic	Phenylketonuria	2023-02-23	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.96; 3Cnet: 1.00). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000102669). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals (PMID: 10234516, 15589814, 24941924, 27121329). A different missense change at the same codon (p.Pro147Leu) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000102670). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Baylor Genetics	RCV000674963	SCV004209577	pathogenic	Phenylketonuria	2023-09-20	criteria provided, single submitter	clinical testing
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000088917	SCV000119515	not provided	not provided		no assertion provided	not provided