Submissions for variant NM_000277.3(PAH):c.940C>A (p.Pro314Thr)

gnomAD frequency: 0.00001  dbSNP: rs199475650

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000672630	SCV004222615	pathogenic	Phenylketonuria	2023-12-30	reviewed by expert panel	curation	The NM_000277.1(PAH):c.940C>A (p.Pro314Thr) variant is a missense variant in exon 9/13 of PAH. It has been found to result in 25% of wild-type PAH enzyme activity in a standard cDNA system and 19% of wild-type PAH enzyme activity in an Intinc system (PMID: 18590700) (PS3_supporting). It has been reported in at least five PKU patients, including those with BH4 deficiency excluded and in trans with Pathogenic variants (PM3_VeryStrong (4.25 points); PP4_Moderate). It has been previously reported in a Taiwanese proband in trans with p.V399V (Pathogenic in ClinVar and per ClinGen PAH VCEP) with mild hyperphenylalanemia and BH4 deficiency excluded by urinary pterins, dihydropteridine reductase activity in erythrocytes, and sequencing of the genes in the BH4 cofactor metabolism pathway (PMID: 14722928). It has also been found in trans with p.V399V (Pathogenic in ClinVar and per ClinGen PAH VCEP) in a Chinese patient with classic PKU (plasma Phe 1230 umol/L) and BH4 deficiency excluded (PMID: 28982351). It has been noted in a Chinese patient with plasma Phe 184 umol/L and BH4 deficiency excluded in trans with a deletion of exons 1-3 (unclassified) (PMID: 29499199). It has been also noted in a Chinese patient with mild hyperphenylalanemia (plasma Phe 148 umol/L) in trans with the p.S70del (Pathogenic in ClinVar and per ClinGen PAH VCEP) variant and in trans with the p.R243Q (Pathogenic in ClinVar and per ClinGen PAH VCEP) variant in a patient with classic PKU (plasma Phe 1561 umol/L); BH4 deficiency was excluded in both cases (PMID: 30459323). Another missense variant at the same site, c.941C>A (p.P314H) is classified as Pathogenic/Likely Pathogenic in ClinVar (ID 102907) (PM5). Two heterozygotes and zero homozygotes for the variant are present in gnomAD, corresponding to a global frequency of 0.00000796 and a maximum population frequency of 0.000109 (South Asian), under the 0.0002 frequency cutoff for use of PM2 (PM2_supporting). The variant is predicted damaging by multiple in-silico predictors, including REVEL (REVEL score 0.867), but tolerated by SIFT; thus, PP3 is not met. Classification: Pathogenic Supporting Criteria: PS3_supporting; PM3_VeryStrong; PM2_supporting; PP4_Moderate
Counsyl	RCV000672630	SCV000797754	likely pathogenic	Phenylketonuria	2018-02-08	criteria provided, single submitter	clinical testing
Invitae	RCV000672630	SCV000962218	pathogenic	Phenylketonuria	2023-08-07	criteria provided, single submitter	clinical testing	This missense change has been observed in individual(s) with hyperphenylalaninemia (PMID: 24401910, 28982351, 29390883). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Pro314 amino acid residue in PAH. Other variant(s) that disrupt this residue have been observed in individuals with PAH-related conditions (PMID: 8807319, 12501224), which suggests that this may be a clinically significant amino acid residue. Experimental studies have shown that this missense change does not substantially affect PAH function (PMID: 18590700). 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 not expected to disrupt PAH protein function. ClinVar contains an entry for this variant (Variation ID: 102904). This variant is present in population databases (rs199475650, gnomAD 0.01%). This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 314 of the PAH protein (p.Pro314Thr).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000672630	SCV004030157	pathogenic	Phenylketonuria	2023-07-17	criteria provided, single submitter	clinical testing	Variant summary: PAH c.940C>A (p.Pro314Thr) results in a non-conservative amino acid change located in the Eukaryotic phenylalanine-4-hydroxylase, catalytic domain (IPR041912) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251290 control chromosomes. c.940C>A has been reported in the literature in the compound heterozygous state in multiple individuals affected with mild hyperphenylalaninemia (MHP) or Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (e.g. Chien_2004, Li_2018, Chen_2018, Wang_2018). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, suggesting reduced enzyme activity of 19-25% compared to wild-type; however, the difference is described as not significant, which does not allow convincing conclusions about the variant effect (Ho_2008). A different variant at the same amino acid position (p.P314H) has also been previously classified by our laboratory as pathogenic. The following publications have been ascertained in the context of this evaluation (PMID: 30459323, 14722928, 18590700, 30050108, 29499199). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV000672630	SCV004209589	pathogenic	Phenylketonuria	2023-09-12	criteria provided, single submitter	clinical testing
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000089168	SCV000119783	not provided	not provided		no assertion provided	not provided