Submissions for variant NM_000277.3(PAH):c.673C>A (p.Pro225Thr)

gnomAD frequency: 0.00001  dbSNP: rs199475589

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000673267	SCV000798450	pathogenic	Phenylketonuria	2018-03-05	criteria provided, single submitter	clinical testing
Invitae	RCV000673267	SCV001236347	pathogenic	Phenylketonuria	2024-01-09	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 225 of the PAH protein (p.Pro225Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hyperphenylalaninemia (PMID: 18299955, 22330942, 23430547). ClinVar contains an entry for this variant (Variation ID: 102779). 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 with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000673267	SCV001338366	pathogenic	Phenylketonuria	2020-02-17	criteria provided, single submitter	clinical testing	Variant summary: PAH c.673C>A (p.Pro225Thr) results in a non-conservative amino acid change located in the Aromatic amino acid hydroxylase, C-terminal (IPR019774) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251338 control chromosomes. c.673C>A has been widely reported in the literature in multiple individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) in literature originating from 1997 (Kozak_1997) through the present (example, Kuznetcova_2019). These data indicate that the variant is very likely to be associated with disease. 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 pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
3billion	RCV000673267	SCV002058376	pathogenic	Phenylketonuria	2022-01-03	criteria provided, single submitter	clinical testing	Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000102779, PMID:9391881, PS1_S). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000102780,VCV000932277, PMID:10394930,10527663,21307867, PM5_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.988, 3CNET: 0.997, PP3_P). A missense variant is a common mechanism associated with Classic phenylketonuria (PP2_P). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000089030	SCV000119635	not provided	not provided		no assertion provided	not provided
Natera, Inc.	RCV000673267	SCV002088649	pathogenic	Phenylketonuria	2021-04-08	no assertion criteria provided	clinical testing