ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.506G>A (p.Arg169His) (rs199475679)

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Total submissions: 12
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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 2018-11-12 criteria provided, single submitter clinical testing The R169H variant in the PAH gene has been reported previously in individuals with non-PKU hyperphenylalaninemia (Desviat et al., 1999; Réblová et al., 2013). The R169H variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R169H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties, and this substitution occurs at a position that is not conserved. However, in silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in the same residue (R169S, R169G, R169C), and multiple nearby residues, have been reported in the Human Gene Mutation Database in association with phenylalanine hydroxylase deficiency disorders (Stenson et al., 2014), supporting the functional importance of this residue and region of the protein. The R169H variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded.
Illumina Clinical Services Laboratory,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
Integrated Genetics/Laboratory Corporation of America RCV000311018 SCV000696452 likely pathogenic Phenylketonuria 2019-06-07 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 0.0003 in 250586 control chromosomes. This frequency is not higher than the expected maximum for a pathogenic variant in PAH causing Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (0.0003 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). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six other submitters, including one expert panel (ClinGen), have provided clinical-significance assessments for this variant in ClinVar after 2014 (without evidence for independent evaluation), and classified the variant as likely pathogenic (4x; including the expert panel) or as VUS (2x). Based on the evidence outlined above, the variant was classified as likely pathogenic.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000088954 SCV000859031 uncertain significance not provided 2018-01-02 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik 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 uncertain significance Phenylketonuria 2019-07-27 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 169 of the PAH protein (p.Arg169His). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs199475679, gnomAD 0.59%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been observed in combination with another PAH variant in several individuals affected with hyperphenylalaninemia (PMID: 10234516, 18299955, 21147011, 26666653, 28982351). Although this variant has a high allele count in the Ashkenazi Jewish population, there have not been frequent reports of Ashkenazi Jewish patients affected with hyperphenylalaninemia in the literature (PMID: 18294361). ClinVar contains an entry for this variant (Variation ID: 102706). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
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

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