Submissions for variant NM_000277.3(PAH):c.1243G>A (p.Asp415Asn)

gnomAD frequency: 0.00011  dbSNP: rs62644499

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000401074	SCV000852091	pathogenic	Phenylketonuria	2018-08-12	reviewed by expert panel	curation	The c.1243G>A (p.Asp415Asn) variant in PAH has been reported in 3 patients with Hyperphenylalaninemia (BH4 deficiency excluded). (PP4_Moderate; PMID: 1358789). This variant has an extremely low allele frequency (0.0001097 in gnomAD) (PM2; http://gnomad.broadinstitute.org). This variant was detected in trans with R408W, F39L, Y414C, IVS10-11G>A (Pathogenic in ClinVar) (PM3_Very-strong; PMID: 1358789; PMID: 12501224; PMID: 18299955). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM3_Very-strong
GeneDx	RCV000088815	SCV000239095	pathogenic	not provided	2021-06-30	criteria provided, single submitter	clinical testing	Reported previously in association with mild hyperphenylalaninemia (Economou-Petersen et al., 1992; Guldberg et al., 1994; Trunzo et al., 2014); Functional studies found that this variant is associated with approximately 35% enzyme activity compared to wild-type (Himmelreich et al., 2018); Associated with BH4 responsiveness (Zurfluh et al., 2008); This variant is associated with the following publications: (PMID: 30037505, 17935162, 31980526, 29499199, 29749107, 12501224, 27264808, 8088845, 24296287, 8929956, 11161839, 8406445, 9634518, 1358789, 22513348, 23500595)
Eurofins Ntd Llc (ga)	RCV000088815	SCV000331012	pathogenic	not provided	2015-11-17	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000000648	SCV000696434	pathogenic	Hyperphenylalaninemia	2016-08-04	criteria provided, single submitter	clinical testing	Variant summary: The PAH c.1243G>A (p.Asp415Asn) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 7/121346 control chromosomes at a frequency of 0.0000577, which does not exceed the estimated maximal expected allele frequency of a pathogenic PAH variant (0.0079057). The variant has been reported in numerous individuals in the literature affected with mild-pku and mild-hyperphenylalaninemia, and has been associated with BH4 responsiveness. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000401074	SCV000834448	pathogenic	Phenylketonuria	2025-01-07	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 415 of the PAH protein (p.Asp415Asn). This variant is present in population databases (rs62644499, gnomAD 0.04%). This missense change has been observed in individual(s) with mild phenylketonuria or mild hyperphenylalaninemia (PMID: 1358789, 18299955, 23932990, 24296287). ClinVar contains an entry for this variant (Variation ID: 617). 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 does not substantially affect PAH function (PMID: 17935162). For these reasons, this variant has been classified as Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000088815	SCV000888341	pathogenic	not provided	2020-12-15	criteria provided, single submitter	clinical testing	This variant is known to be associated with hyperphenylalaninemia and mild PKU. It is associated with residual PAH expression and activity and has been reported as compound heterozygous in multiple individuals with BH4-responsive hyperphenylalaninemia or mild PKU (PMID: 30037505 (2018), 27469133 (2017), 26666653 (2015), 24296287 (2014), 23932990 (2013), 17935162 (2008), 9634518 (1998), 9399896 (1997)).
Fulgent Genetics, Fulgent Genetics	RCV000401074	SCV000893264	pathogenic	Phenylketonuria	2021-08-23	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000401074	SCV000914552	pathogenic	Phenylketonuria	2018-08-20	criteria provided, single submitter	clinical testing	Across a selection of available literature, the PAH c.1243G>A (p.Asp415Asn) missense variant has been identified in a compound heterozygous state in 19 patients (Economou-Petersen et al. 1992; Guldberg et al. 1994; Guldberg et al. 1995; Bercovich et al. 2008; Trunzo et al. 2014; Ho et al. 2014; Jeannesson-Thivisol et al. 2015). The p.Asp415Asn variant was absent from 220 controls and is reported at a frequency of 0.000358 in the Latino population of the Genome Aggregation Database. In vivo analysis of phenylalanine loading demonstrates that affected individuals with the p.Asp415Asn variant in a compound heterozygous state with a null PAH variant were able to clear the dose in 24 hours, which was consistent with the disease phenotype, and was established in several individuals affected by PAH deficiency (Economou-Petersen et al. 1992; Guldberg et al. 1995). Based on the evidence, the p.Asp415Asn variant is classified as pathogenic for phenylalanine hydroxylase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Baylor Genetics	RCV000401074	SCV001163709	pathogenic	Phenylketonuria	2024-03-30	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000401074	SCV001194126	pathogenic	Phenylketonuria	2019-12-20	criteria provided, single submitter	clinical testing	NM_000277.1(PAH):c.1243G>A(D415N) is classified as pathogenic in the context of phenylalanine hydroxylase deficiency and can be associated with variant or non-PKU hyperphenylalaninemia. Sources cited for classification include the following: PMID 1358789, 23500595, 24296287, 17935162, 12501224, 22513348, 9781015, 18299955, 18294361, 8088845 and 10234516. Classification of NM_000277.1(PAH):c.1243G>A(D415N) 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.
CeGaT Center for Human Genetics Tuebingen	RCV000088815	SCV001247318	pathogenic	not provided	2019-05-01	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000401074	SCV002016508	pathogenic	Phenylketonuria	2022-06-07	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003415609	SCV004115586	pathogenic	PAH-related disorder	2023-03-11	criteria provided, single submitter	clinical testing	The PAH c.1243G>A variant is predicted to result in the amino acid substitution p.Asp415Asn. This variant has been reported in the heterozygous state with a second PAH pathogenic variant in numerous patients with mild hyperphenylalaninemia (MHP) (e.g., Economou-Petersen et al. 1992. PubMed ID: 1358789; Guldberg et al. 1996. PubMed ID: 8929956; Zhu et al. 2013. PubMed ID: 23932990; Trunzo et al. 2014. PubMed ID: 24296287; Jeannesson-Thivisol et al. 2015. PubMed ID: 26666653). We have also observed this variant internally, in the homozygous or presumed compound heterozygous state with a second pathogenic variant, in five patients with a biochemical or clinical diagnosis of hyperphenylalaninemia. In functional studies, the p.Asp415Asn substitution has been reported to reduce enzyme activity, with the BioPKU database reporting an average residual enzyme activity of 72% (Zurflüh et al. 2008. PubMed ID: 17935162; Himmelreich et al. 2018. PubMed ID: 30037505; http://www.biopku.org/pah/result-details-pah.asp?ID=582). The c.1243G>A (p.Asp415Asn) has been classified as ‘Pathogenic’ by the ClinGen PAH Variant Curation Expert Panel, as well as by several other outside laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/617/). Based on these observations, we classify this variant as pathogenic.
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000401074	SCV005051915	pathogenic	Phenylketonuria	2024-02-01	criteria provided, single submitter	curation
Mayo Clinic Laboratories, Mayo Clinic	RCV000088815	SCV005414099	pathogenic	not provided	2024-06-25	criteria provided, single submitter	clinical testing	PP4_moderate, PM2_moderate, PM3_very_strong
OMIM	RCV000000648	SCV000020798	pathogenic	Hyperphenylalaninemia	1992-09-01	no assertion criteria provided	literature only
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000088815	SCV000119406	not provided	not provided		no assertion provided	not provided
Natera, Inc.	RCV000401074	SCV001458995	pathogenic	Phenylketonuria	2020-09-16	no assertion criteria provided	clinical testing