Submissions for variant NM_000277.3(PAH):c.506G>A (p.Arg169His)

gnomAD frequency: 0.00020  dbSNP: rs199475679

Total submissions: 23

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000311018	SCV000852129	likely pathogenic	Phenylketonuria	2018-08-10	reviewed by expert panel	curation	PAH-specific ACMG/AMP criteria applied: PP4_Moderate: This variant has been reported in multiple mild hyperphenylalaninaemia (MHP) patients, with BH4 defects excluded. Upgraded per ClinGen Metabolic workgroup. (PMID:10234516); PM3_Strong: Detected with P281L and A403V, both pathogenic variants (PMID:10234516). In summary this variant meets criteria to be classified as likely pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PP4_Moderate, PM3_Strong).
GeneDx	RCV000088954	SCV000239055	pathogenic	not provided	2024-05-23	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29789446, 29316886, 23357515, 26982749, 21147011, 12655553, 18294361, 11385716, 19015950, 33677757, 30311390, 29499199, 31355225, 34426522, 33101986, 18299955, 17924342, 31980526, 32668217, 26666653, 10234516, 35405047, 35355500, 34405919, 28982351, 31623983, 30050108, 26582918, 29997390, 35281663, 38706300, 38731816, 31947737, 37837865)
Illumina Laboratory Services, Illumina	RCV000311018	SCV000375569	likely pathogenic	Phenylketonuria	2018-05-04	criteria provided, single submitter	clinical testing	The PAH c.506G>A (p.Arg169His) missense variant has been reported in five studies in which it is found in a total of six patients with phenylalanine hydroxylase (PAH) deficiency including in two in a compound heterozygous state with another missense variant, two in heterozygous state with a mild form of phenylalanine hydroxylase deficiency, and two with unknown zygosity (Desviat et al. 1999; Aulehla-Scholz et al. 2003; Bercovich et al. 2008a; Bercovich et al. 2008b; Réblová et al. 2013). The p.Arg169His variant was absent from at least 200 controls and is reported at a frequency of 0.00046 in the European (non-Finnish) population of the Exome Aggregation Consortium. Based on the evidence, the p.Arg169His variant is classified as likely pathogenic for phenylalanine hydroxylase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Genetic Services Laboratory, University of Chicago	RCV000311018	SCV000596206	likely pathogenic	Phenylketonuria	2016-07-18	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001530926	SCV000696452	pathogenic	6-Pyruvoyl-tetrahydrobiopterin synthase deficiency	2021-06-28	criteria provided, single submitter	clinical testing	Variant summary: PAH c.506G>A (p.Arg169His) results in a non-conservative amino acid change located in the Aromatic amino acid hydroxylase, C-terminal domain (IPR019774) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00026 in 395274 control chromosomes in the gnomAD database (v2.1 and v3.1 datasets), including 1 homozygote. This frequency is not higher than the maximum expected for a pathogenic variant in PAH causing Hyperphenylalaninemia (0.00026 vs 0.0079), allowing no conclusion about variant significance. c.506G>A, has been reported in the literature in multiple mild hyperphenylalaninaemia (MHP) patients with another pathogenic variant on the other allele (e.g. Desviat_1999, Bercovich_2008, Jeannesson-Thivisol_2015, Liu_2017, Garbade_2019, Rajabi_2019, Ngiwsara_2021). In addition, a recent meta-analysis reported the variant in several compound heterozygous patients and in one homozygote, in association with MHP, and an allelic phenotype value of 10 (Hillert_2020). At least one publication reported experimental evidence evaluating an impact on protein function, and demonstrated that the variant had a residual activity of 52% of the wild type enzyme (Ngiwsara_2021). Nine other submitters, including one expert panel (ClinGen), have provided clinical-significance assessments for this variant in ClinVar after 2014 and classified the variant as likely pathogenic (n=6; including the expert panel), pathogenic (n=1) and VUS (n=2). Based on the evidence outlined above, the variant was classified as pathogenic.
Eurofins Ntd Llc (ga)	RCV000088954	SCV000859031	uncertain significance	not provided	2018-01-02	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000088954	SCV001148806	likely pathogenic	not provided	2019-04-01	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000311018	SCV001163724	pathogenic	Phenylketonuria	2024-03-30	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000311018	SCV001245021	pathogenic	Phenylketonuria	2018-10-12	criteria provided, single submitter	clinical testing	A heterozygous missense variant, NM_000277.1(PAH):c.506G>A, has been identified in exon 5 of 13 of the PAH gene. The variant is predicted to result in a minor amino acid change from an arginine to a histidine at position 169 of the protein, NP_000268.1(PAH):p.(Arg169His). The arginine residue at this position has moderate conservation (100 vertebrates, UCSC), and is located within the Biopterin domain. In silico predictions of pathogenicity for this variant are conflicting (Polyphen, SIFT, CADD, Mutation Taster). The variant is present in the gnomAD database at a frequency of 0.029% (78 heterozygotes, 1 homozygote). The variant has previously been described as pathogenic or VUS in multiple patients with mild phenylalanine hydroxylase deficiency (ClinVar). Different variants in the same codon resulting in a change to proline and cysteine, p.(Arg169Pro) and p.(Arg169Cys) have been reported in patients with phenylketonuria (ClinVar). Analysis of parental samples indicated this variant was paternally inherited and to be present in cis with the second reported PAH variant. Based on the information available at the time of curation, this variant has been classified as PATHOGENIC. <br />
Labcorp Genetics (formerly Invitae), Labcorp	RCV000311018	SCV001412402	pathogenic	Phenylketonuria	2024-11-06	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 169 of the PAH protein (p.Arg169His). This variant is present in population databases (rs199475679, gnomAD 0.7%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with hyperphenylalaninemia (PMID: 10234516, 18299955, 21147011, 26666653, 28982351). ClinVar contains an entry for this variant (Variation ID: 102706). 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%. This variant disrupts the p.Arg169 amino acid residue in PAH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 26503515, 29499199, 30050108). 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.
Revvity Omics, Revvity	RCV000311018	SCV002016484	pathogenic	Phenylketonuria	2023-08-07	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV000311018	SCV002579864	likely pathogenic	Phenylketonuria	2022-01-04	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000311018	SCV002789317	likely pathogenic	Phenylketonuria	2021-11-03	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002515783	SCV003686790	likely pathogenic	Inborn genetic diseases	2022-02-01	criteria provided, single submitter	clinical testing	The c.506G>A (p.R169H) alteration is located in exon 5 (coding exon 5) of the PAH gene. This alteration results from a G to A substitution at nucleotide position 506, causing the arginine (R) at amino acid position 169 to be replaced by a histidine (H). Based on data from gnomAD, the A allele has an overall frequency of 0.03% (77/281982) total alleles studied. The highest observed frequency was 0.59% (61/10348) of Ashkenazi Jewish alleles. This alteration has been reported in the compound heterozygous state with a second PAH alteration in multiple patients with hyperphenylalaninemia (Desviat, 1999; Dobrowolski, 2011; Jeannesson-Thivisol, 2015; Liu, 2017; Rajabi, 2019). This amino acid position is highly conserved in available vertebrate species. Based on internal structural analysis, R169H is deleterious. The variant is mildly destabilizing to the local structure. The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as likely pathogenic.
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV003987362	SCV004804752	pathogenic	Pulmonary hypertension, primary, 1	2024-03-17	criteria provided, single submitter	research
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV000311018	SCV004807888	pathogenic	Phenylketonuria	2024-03-23	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000311018	SCV004848712	pathogenic	Phenylketonuria	2022-06-30	criteria provided, single submitter	clinical testing	The p.Arg169His variant in PAH has been reported in 18 individuals with phenylalanine hydroxylase deficiency including 16 compound heterozygotes and one homozygote (Desviat 1999 PMID: 10234516, Wang 2018 PMID: 29499199, Su 2019 PMID: 31355225, Hillert 2020 PMID: 32668217), many of whom presented with classical phenylketo It has also been identified 0.55% (19/3472) of Ashkenazi Jewish chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant has been reported in ClinVar as likely pathogenic by the ClinGen PAH Variant Curation Expert Panel using the . ACMG-AMP criteria specific for phenylalanine hydroxylase variants (Zastrow 2018 PMID: 30311390) and is curated in the FDA-recognized human genetic variant database (Variation ID 102706). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. Three additional variants involving this codon (p.Arg169Ser, p.Arg169Gly, and p.Arg169Cys) have been identified in individuals with phenylalanine hydroxylase deficiency and are classified as likely pathogenic or pathogenic by the ClinGen PAH Variant Curation Expert Panel. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive phenylalanine hydroxylase deficiency. ACMG/AMP Criteria applied: PP4_Moderate, PM5, BS1_Supporting, PM3_VeryStrong.
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000311018	SCV005051898	likely pathogenic	Phenylketonuria	2024-02-01	criteria provided, single submitter	curation
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000088954	SCV000119556	not provided	not provided		no assertion provided	not provided
Counsyl	RCV000311018	SCV000800747	likely pathogenic	Phenylketonuria	2019-01-11	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000311018	SCV001455100	likely pathogenic	Phenylketonuria	2020-09-16	no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000088954	SCV001953043	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000088954	SCV001967069	uncertain significance	not provided		no assertion criteria provided	clinical testing