Submissions for variant NM_000277.3(PAH):c.1223G>A (p.Arg408Gln)

gnomAD frequency: 0.00004  dbSNP: rs5030859

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000000643	SCV000852159	pathogenic	Phenylketonuria	2018-08-05	reviewed by expert panel	curation	PAH-specific ACMG/AMP criteria applied: PM3_Strong: In trans with R408W, IVS4-1G>A, R241C (ClinGen, P) (PMID:1312992; PMID:14722928); PP3: ; PS3: Mutant enzyme activity of 46% in BioPKU (PMID:9860305); PP4_Moderate: ~830 uml/L w/o BH4 deficiency & 823 umol/L, BH4 status unknown (PMID:9860305; PMID:1312992). 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: (PM3_Strong, PP3, PS3, PP4_Moderate).
Eurofins Ntd Llc (ga)	RCV000088806	SCV000225501	pathogenic	not provided	2017-06-29	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000000643	SCV000830376	pathogenic	Phenylketonuria	2025-01-21	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 408 of the PAH protein (p.Arg408Gln). This variant is present in population databases (rs5030859, gnomAD 0.03%). This missense change has been observed in individual(s) with PAH-related disease (PMID: 1312992, 10471838, 24401910, 29317692). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 612). 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 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: 12655546). This variant disrupts the p.Arg408 amino acid residue in PAH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 2014036, 12173030, 24401910). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000000643	SCV000919913	pathogenic	Phenylketonuria	2018-01-08	criteria provided, single submitter	clinical testing	Variant summary: The PAH c.1223G>A (p.Arg408Gln) variant located in the Aromatic amino acid hydroxylas, C-terminal domain (InterPro) involves the alteration of a conserved nucleotide and 4/5 in silico tools predict a damaging outcome for this variant. This variant was found in 13/277144 control chromosomes (gnomAD) at a frequency of 0.0000469, 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 compound heterozygous individuals, presenting with a significant decrease in PAH activity. In support of this, there are other variants at the 408 codon that have been reported in patients with PKU (R408L, R408W), suggesting the codon is important for function. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Baylor Genetics	RCV000000643	SCV001163710	pathogenic	Phenylketonuria	2024-03-26	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000000643	SCV001194182	pathogenic	Phenylketonuria	2019-12-19	criteria provided, single submitter	clinical testing	NM_000277.1(PAH):c.1223G>A(R408Q) is classified as pathogenic in the context of phenylalanine hydroxylase deficiency and can be associated with variant or non-PKU HPA. Sources cited for classification include the following: PMID 14722928, 1312992, 1355066, 1301200, and 8533759. Classification of NM_000277.1(PAH):c.1223G>A(R408Q) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Revvity Omics, Revvity	RCV000000643	SCV002016494	pathogenic	Phenylketonuria	2021-07-26	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000000643	SCV002768000	pathogenic	Phenylketonuria	2021-05-06	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with phenylketonuria (PKU; MIM#261600). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to glutamine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 14 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (252 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated catalytic domain (PMID: 30037505). (I) 0705 - The well-reported pathogenic variant, p.(Arg408Trp), affecting the same residue has previously been reported in association with phenylketonuria (ClinVar), however it is not considered a comparable variant as it has a major Grantham score, whereas this variant has a minor score, therefore cannot be used to inform pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in multiple individuals with mild PKU, mild hyperphenylalaninemia ( MHP) and non-PKU hyperphenylalaninemia (ClinVar, PMID: 1312992). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Site-directed mutagenesis studies have shown a reduction of 41% in PAH activity compared to wild-type (PMID: 30037505). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Fulgent Genetics, Fulgent Genetics	RCV000000643	SCV002810394	pathogenic	Phenylketonuria	2021-12-15	criteria provided, single submitter	clinical testing
Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	RCV004798710	SCV002818166	pathogenic	Hyperphenylalaninemia	2024-10-04	criteria provided, single submitter	research	PM3_VeryStrong, PM2, PP4, PS3
Cellular and Molecular Medicine Research Institute, Urmia University of Medical Sciences	RCV000000643	SCV004035236	pathogenic	Phenylketonuria	2023-09-19	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000088806	SCV005414101	pathogenic	not provided	2024-02-27	criteria provided, single submitter	clinical testing	PP3, PP4_moderate, PM3_strong, PS3
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV000000643	SCV005417092	pathogenic	Phenylketonuria		criteria provided, single submitter	clinical testing	PM2_Supporting+PM3_VeryStrong+PS3+PM5
GeneDx	RCV000088806	SCV005690084	pathogenic	not provided	2023-06-28	criteria provided, single submitter	clinical testing	Functional studies of the R408Q variant show significantly reduced enzyme activity compared to wildtype (PMID: 26803807); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 22975760, 21953985, 21228398, 10471838, 25750018, 24327145, 17935162, 12655546, 1312992, 23891399, 1355066, 1301200, 29102225, 29317692, 24401910, 14722928, 28676969, 29499199, 30037505, 29413232, 29316886, 30747360, 31355225, 30275481, 33677757, 32668217, 32778825, 35314707, 16253218, 33161754, 36703223, 36646061, 36755623, 36787440, 37443404, 36845377, 38105685, 26803807, 25596310)
OMIM	RCV000000643	SCV000020793	pathogenic	Phenylketonuria	1992-08-01	no assertion criteria provided	literature only
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000088806	SCV000119396	not provided	not provided		no assertion provided	not provided
Natera, Inc.	RCV000000643	SCV001458998	pathogenic	Phenylketonuria	2020-09-16	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003934788	SCV004750289	pathogenic	PAH-related disorder	2024-02-16	no assertion criteria provided	clinical testing	The PAH c.1223G>A variant is predicted to result in the amino acid substitution p.Arg408Gln. This variant has been reported in the homozygous state or with a second pathogenic PAH variant in many patients with phenylalanine hydroxylase deficiency (e.g., Zschocke et al. 1995. PubMed ID: 8533759; Eiken et al. 1996. PubMed ID: 8875186; Table S3, Hillert et al. 2020. PubMed ID: 32668217). The p.Arg408Gln amino acid substitution has been reported to reduce PAH enzyme activity to ~50% of wild-type (Zurflüh et al. 2008. PubMed ID: 17935162) and is generally considered a mild PAH variant (Liang et al. 2014. PubMed ID: 24401910). This variant has been classified as pathogenic by the ClinGen PAH Variant Curation Expert Panel as well as several other outside laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/612/). Over twenty patients homozygous for the c.1223G>A (p.Arg408Gln) variant have been reported in the BioPKU database; the majority of these patients presented with mild hyperphenylalaninemia or mild PKU (http://www.biopku.org). In summary, we classify the c.1223G>A variant as pathogenic.
Neonatal Disease Screening Center, Medical Genetics Center, Huaihua City Maternal and Child Health Care Hospital	RCV000000643	SCV004800860	pathogenic	Phenylketonuria		no assertion criteria provided	clinical testing	PS3+PM3_VS+PM5+PP1+PP3+PP4_M