ClinVar Miner

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

gnomAD frequency: 0.00006  dbSNP: rs199475679
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Total submissions: 17
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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 likely pathogenic not provided 2022-08-16 criteria provided, single submitter clinical testing Reported as likely pathogenic by the ClinGen PAH Variant Curation Expert Panel FDA Recognized Database (ClinVar SCV000852129.3; Landrum et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; 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)
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 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 />
Invitae RCV000311018 SCV001412402 pathogenic Phenylketonuria 2021-12-19 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). 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. 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.
MGZ Medical Genetics Center RCV000311018 SCV002579864 likely pathogenic Phenylketonuria 2022-01-04 criteria provided, single submitter clinical testing
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
PerkinElmer Genomics RCV000311018 SCV002016484 pathogenic Phenylketonuria 2020-11-23 no assertion criteria provided clinical testing

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