Submissions for variant NM_000277.3(PAH):c.199T>C (p.Ser67Pro)

dbSNP: rs5030842

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV001260324	SCV004015303	pathogenic	Phenylketonuria	2023-03-16	reviewed by expert panel	curation	The c.199T>C (p.Ser67Pro) variant in PAH has been reported in multiple individuals with PKU (BH4 deficiency excluded). (PP4_Moderate; 8533759; 26351554). This variant has an extremely low allele frequency in ExAC (MAF=0.00002, PM2). This variant was detected in trans with L48S (PMID: 8592329), IVS10-11G>A, R408Q (P), R261Q, R252W (P/LP) PMID: 26351554 (PM3_VS). Multiple lines of computational evidence support a deleterious effect (SIFT, PolyPhen-2, MutationTaster, REVEL=0.954) (PP3). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_VS, PM2, PP4_Moderate, PP3.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000088867	SCV000888346	pathogenic	not provided	2018-04-05	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001260324	SCV001437249	likely pathogenic	Phenylketonuria	2020-09-21	criteria provided, single submitter	clinical testing	Variant summary: PAH c.199T>C (p.Ser67Pro) results in a non-conservative amino acid change located in the ACT domain (IPR002912) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251284 control chromosomes. c.199T>C has been reported in the literature in multiple individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) and has been subsequently cited by others (example, Daniele_2006, Bik-Multanowski_2013, Bagheri_2015). These data indicate that the variant is very likely to be associated with disease. However, to our knowledge, no concrete experimental evidence demonstrating an impact on protein function was ascertained in the context of this classification. 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 likely pathogenic.
Invitae	RCV001260324	SCV002246406	pathogenic	Phenylketonuria	2021-05-12	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. 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. This variant has been observed in individual(s) with hyperphenylalaninemia (PMID: 12409276, 16198137, 19292873, 19913839). ClinVar contains an entry for this variant (Variation ID: 102625). This variant is present in population databases (rs5030842, ExAC 0.002%). This sequence change replaces serine with proline at codon 67 of the PAH protein (p.Ser67Pro). The serine residue is highly conserved and there is a moderate physicochemical difference between serine and proline.
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000088867	SCV000119463	not provided	not provided		no assertion provided	not provided