Submissions for variant NM_000277.3(PAH):c.364C>T (p.Pro122Ser)

dbSNP: rs1466564208

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV001269311	SCV001448660	likely pathogenic	Phenylketonuria	2020-07-24	reviewed by expert panel	curation	The c.364C>T (p.Pro122Ser) missense variant in PAH was reported in a Spanish patient with Mild HPA. A defect in the synthesis or regeneration in the pathways of 6R-BH4 was ruled out by analyzing urinary pterin levels and measuring dihydropteridine reductase activity. This variant was detected in trans with pathogenic variant p.Asp415Asn (PMID 27121329). It was found at extremely low frequency in gnomAD (MAF=0.00003) and predicted deleterious using in silico data. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3, PP4 moderate, and PP3.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001269311	SCV002247259	pathogenic	Phenylketonuria	2023-09-03	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. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Pro122 amino acid residue in PAH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10598814, 12655546). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 987906). This missense change has been observed in individual(s) with phenylketonuria (PMID: 23514811). This variant is present in population databases (no rsID available, gnomAD 0.003%). This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 122 of the PAH protein (p.Pro122Ser).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001269311	SCV005185168	likely pathogenic	Phenylketonuria	2024-05-31	criteria provided, single submitter	clinical testing	Variant summary: PAH c.364C>T (p.Pro122Ser) results in a non-conservative amino acid change located in the Aromatic amino acid hydroxylase, C-terminal domain (IPR019774) 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 251390 control chromosomes. c.364C>T has been reported in the literature in compound heterozygous individuals affected with mild or classic Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (e.g. Bueno_2013, Chen_2018). These data indicate that the variant may be associated with disease. A different variant affecting the same codon has been classified as pathogenic by our lab (c.365C>A, p.Pro122Gln), supporting the critical relevance of codon 122 to PAH protein function. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 23514811, 30459323). ClinVar contains an entry for this variant (Variation ID: 987906). Based on the evidence outlined above, the variant was classified as likely pathogenic.