Submissions for variant NM_000277.3(PAH):c.941C>A (p.Pro314His)

gnomAD frequency: 0.00001  dbSNP: rs62642940

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000409567	SCV004222614	pathogenic	Phenylketonuria	2023-12-30	reviewed by expert panel	curation	The NM_000277.1(PAH):c.941C>A (p.Pro314His) variant is a missense variant in exon 9/13 of PAH. It has been found to result in 15% of wild-type PAH enzyme activity in a standard cDNA system and 5% of wild-type PAH enzyme activity in an Intinc system (PMID: 18590700) (PS3_supporting). It has been noted in at least five patients, including in trans with Pathogenic or Likely Pathogenic variants and among those whom BH4 deficiency had been excluded (PM3_VeryStrong (4.25 points total); PP4_Moderate). It has been previously reported in a Mexican patient with mild hyperphenylalanemia in trans with the c.809G>A (p.Arg270Lys) variant (Pathogenic in ClinVar) (PMID: 24941924). It has been noted in 3 PKU patients: one in trans with the p.I94del variant (unclassified) and in two in trans with the p.Y277D variant (Pathogenic in ClinVar and per ClinGen PAH VCEP) (PMID: 23842451). It has been found in a patient with mild hyperphenylalanemia (plasma Phe 456 umol/L) and BH4 deficiency excluded, in trans with the p.R155H variant (Pathogenic in ClinVar and per ClinGen PAH VCEP) (PMID: 28593914). The variant is absent from ethnically diverse control databases, including gnomAD/ExAC, 1000 Genomes, and ESP (PM2_supporting). The variant is predicted damaging by multiple in-silico missense predictors, including REVEL (REVEL score 0.91) (PP3). Classification: Pathogenic Supporting Criteria: PS3_supporting; PM2_supporting; PM3_VeryStrong; PP4_Moderate; PP3
Counsyl	RCV000409567	SCV000486619	likely pathogenic	Phenylketonuria	2016-07-12	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000409567	SCV000744093	pathogenic	Phenylketonuria	2014-10-08	criteria provided, single submitter	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000409567	SCV000745571	likely pathogenic	Phenylketonuria	2016-01-04	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000409567	SCV001363421	pathogenic	Phenylketonuria	2019-08-29	criteria provided, single submitter	clinical testing	Variant summary: PAH c.941C>A (p.Pro314His) results in a non-conservative amino acid change located in the catalytic domain (IPR041912) 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 251290 control chromosomes (gnomAD). c.941C>A has been reported in the literature in multiple individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (e.g. Guldberg_1998, Anjema_2013, Vela-Amieva_2015). These data indicate that the variant is very likely to be associated with disease. A publication reported experimental evidence using an in vitro expression system, and demonstrated that the variant significantly reduced enzyme activity, as well as (in addition to its protein level effects) it also increased exon 9 skipping by disrupting exonic splicing enhancer (ESE) motifs (Ho_2008). Two ClinVar submissions (evaluation after 2014) cite the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000409567	SCV001414760	pathogenic	Phenylketonuria	2023-09-01	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 102907). 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 missense change has been observed in individual(s) with phenylketonuria (PMID: 8807319). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with histidine, which is basic and polar, at codon 314 of the PAH protein (p.Pro314His). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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 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. Experimental studies have shown that this missense change affects PAH function (PMID: 18590700).
Revvity Omics, Revvity	RCV000409567	SCV002020221	likely pathogenic	Phenylketonuria	2019-04-05	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000409567	SCV005053803	pathogenic	Phenylketonuria	2024-03-30	criteria provided, single submitter	clinical testing
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000089171	SCV000119786	not provided	not provided		no assertion provided	not provided