Submissions for variant NM_000277.3(PAH):c.1238G>C (p.Arg413Pro)

dbSNP: rs79931499

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000000623	SCV000852136	pathogenic	Phenylketonuria	2018-08-05	reviewed by expert panel	curation	PAH-specific ACMG/AMP criteria applied: PS3: In vitro expression of altered protein in COS cells produces severe decrease of PAH activity (<3%); PM2: Extremely low frequency. ExAC MAF=0.00012; PP4_Moderate: Detected in PKU patients, BH4 deficiency excluded; PP3: Predicted deleterious in SIFT, Polyphen-2, MutationTaster. REVEL=0.895; PM3: Detected with V388M (pathogenic) in 2 patients (PMID:9860305; PMID:21307867). In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PS3, PM2, PP4_Moderate, PP3, PM3).
Counsyl	RCV000000623	SCV000486282	pathogenic	Phenylketonuria	2016-05-04	criteria provided, single submitter	clinical testing
GeneDx	RCV000088813	SCV000521188	pathogenic	not provided	2023-06-28	criteria provided, single submitter	clinical testing	Functional studies found this variant is associated with severely diminished or completely absent of PAH enzyme activity compared to wildtype, supporting a damaging effect (Himmelreich et al., 2018; Wang et al., 1991); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Classified as responsive to tetrahydrobiopterin (BH4) therapy (Zurfluh et al. 2008); This variant is associated with the following publications: (PMID: 14654665, 8051931, 27173423, 29413232, 34704413, 29499199, 24401910, 21953985, 1301187, 2006152, 27264808, 25750018, 8929956, 25550961, 10484807, 9048935, 29317692, 30221392, 31355225, 30747360, 30275481, 26322415, 21307867, 15319459, 9860305, 1998345, 33677757, 32668217, 32778825, 30037505, 35314707, 29353259, 35405047, 33161754, 17935162, 16253218)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000000623	SCV000696433	pathogenic	Phenylketonuria	2016-08-05	criteria provided, single submitter	clinical testing	Variant summary: The PAH c.1238G>C (p.Arg413Pro) variant causes a missense change involving a non-conserved nucleotide with 5/5 in silico tools predicting a damaging outcome. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency 1/121344, which does not exceed the estimated maximal expected allele frequency for a pathogenic PAH variant of 1/126. The variant of interest was found in multiple affected individuals diagnosed with classic PKU via publications and has been indicated that it is predominantly observed in populations of Asian origin. In addition, publications indicated that the patients showed zero PAH activity. In addition, multiple databases/clinical laboratories cite the variant as "pathogenic." Therefore, the variant of interest has been classified as "pathogenic."
Eurofins Ntd Llc (ga)	RCV000088813	SCV000706081	pathogenic	not provided	2017-02-07	criteria provided, single submitter	clinical testing
Invitae	RCV000000623	SCV001227804	pathogenic	Phenylketonuria	2024-01-08	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 413 of the PAH protein (p.Arg413Pro). This variant is present in population databases (rs79931499, gnomAD 0.006%). This missense change has been observed in individual(s) with PAH-related disease (PMID: 24401910, 27264808). ClinVar contains an entry for this variant (Variation ID: 592). 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 with a positive predictive value of 80%. Experimental studies have shown that this missense change affects PAH function (PMID: 17935162, 21953985). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV000000623	SCV004201329	pathogenic	Phenylketonuria	2023-10-27	criteria provided, single submitter	clinical testing
OMIM	RCV000000623	SCV000020773	pathogenic	Phenylketonuria	1991-03-01	no assertion criteria provided	literature only
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000088813	SCV000119403	not provided	not provided		no assertion provided	not provided
Natera, Inc.	RCV000000623	SCV001458997	pathogenic	Phenylketonuria	2020-09-16	no assertion criteria provided	clinical testing