Submissions for variant NM_000277.3(PAH):c.890G>A (p.Arg297His)

gnomAD frequency: 0.00003  dbSNP: rs62642939

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000150085	SCV001146750	pathogenic	Phenylketonuria	2019-07-07	reviewed by expert panel	curation	The c.890G>A (p.Arg297His) variant in PAH has been reported in 6 patients with PKU, in trans with established pathogenic variants (PMID: 9298832,24401910) with BH4 deficiency excluded in one (PMIDs 24401910 & 9298832). This variant has an extremely low allele frequency in gnomAD (2/245792). The arginine at position 297 is in the C-terminal aromatic amino acid hydroxylase domain, and computational prediction tools and conservation analysis suggest that the c.890G>A variant may impact the protein function. Mutant enzyme activity is 20% as compared to wild type (PMID:24401910). Overall, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP3, PP4_moderate, PM2, PM3_strong, PS3.
Eurofins Ntd Llc (ga)	RCV000078535	SCV000110391	pathogenic	not provided	2012-12-21	criteria provided, single submitter	clinical testing
Counsyl	RCV000150085	SCV000485321	pathogenic	Phenylketonuria	2015-11-17	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000588535	SCV000696469	pathogenic	Hyperphenylalaninemia	2017-08-11	criteria provided, single submitter	clinical testing	Variant summary: The PAH c.890G>A (p.Arg297His) variant located in the aromatic amino acid hydroxylase, C-terminal domain (via InterPro) involves the alteration of a conserved nucleotide and 4/5 in silico tools predict a damaging outcome. A functional study, Liang_2014, supports these predictions finding the variant to significantly decreased PAH activity. This variant was found in 1/121030 control chromosomes at a frequency of 0.0000083, which does not exceed the estimated maximal expected allele frequency of a pathogenic PAH variant (0.0079057). Multiple publications have cited the variant in affected individuals with mild forms of hyperphenylalaninemia. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000150085	SCV000893940	pathogenic	Phenylketonuria	2018-10-31	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000150085	SCV001206964	pathogenic	Phenylketonuria	2025-01-08	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 297 of the PAH protein (p.Arg297His). This variant is present in population databases (rs62642939, gnomAD 0.006%). This missense change has been observed in individual(s) with hyperphenylalaninemia (PMID: 9298832, 16198137, 23430547, 24401910, 25596310). ClinVar contains an entry for this variant (Variation ID: 92750). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt PAH protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects PAH function (PMID: 24401910, 30037505). This variant disrupts the p.Arg297 amino acid residue in PAH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8807331, 10234516, 21307867, 23357515, 27121329). 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.
CeGaT Center for Human Genetics Tuebingen	RCV000078535	SCV001334784	pathogenic	not provided	2020-02-01	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000150085	SCV004209665	pathogenic	Phenylketonuria	2024-01-28	criteria provided, single submitter	clinical testing
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV000150085	SCV004804990	pathogenic	Phenylketonuria	2024-03-17	criteria provided, single submitter	research
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000150085	SCV005200806	pathogenic	Phenylketonuria	2024-05-20	criteria provided, single submitter	clinical testing	PP3, PP4_moderate, PM2, PM3_strong, PS3
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000078535	SCV000119758	not provided	not provided		no assertion provided	not provided
Natera, Inc.	RCV000150085	SCV001463136	pathogenic	Phenylketonuria	2020-09-16	no assertion criteria provided	clinical testing