Submissions for variant NM_000277.3(PAH):c.940C>T (p.Pro314Ser)

dbSNP: rs199475650

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000758098	SCV000886568	pathogenic	Phenylketonuria	2018-12-09	reviewed by expert panel	curation	The c.940C>T (p.Pro314Ser) variant in PAH is absent in population databases, and is in the same codon as two previously described Pathogenic/Likely pathogenic variants (p.Pro314His and p.Pro314Thr). It has been found in trans with a pathogenic variant (p.R408W) in a patient with PAH deficiency (BH4 defects excluded, PMID: 12501224). Functional studies showed it has 26% enzyme activity compared to wild type controls. PMID: 18590700. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PS3, PM2, PM3, PM5.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000758098	SCV002244459	pathogenic	Phenylketonuria	2021-10-22	criteria provided, single submitter	clinical testing	This missense change has been observed in individual(s) with hyperphenylalaninemia (PMID: 12501224, 32668217). ClinVar contains an entry for this variant (Variation ID: 102905). 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. Experimental studies have shown that this missense change affects PAH function (PMID: 18538294). This variant disrupts the p.Pro314 amino acid residue in PAH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 24401910, 28982351, 29390883). 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. This variant is not present in population databases (ExAC no frequency). This sequence change replaces proline with serine at codon 314 of the PAH protein (p.Pro314Ser). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and serine.
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000089169	SCV000119784	not provided	not provided		no assertion provided	not provided