ClinVar Miner

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

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Total submissions: 8
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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).
Counsyl RCV000311018 SCV000800747 uncertain significance Phenylketonuria 2018-05-09 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
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000088954 SCV000859031 uncertain significance not provided 2018-01-02 criteria provided, single submitter clinical testing
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.
Genetic Services Laboratory, University of Chicago RCV000311018 SCV000596206 likely pathogenic Phenylketonuria 2016-07-18 criteria provided, single submitter clinical testing
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.
Integrated Genetics/Laboratory Corporation of America RCV000311018 SCV000696452 likely pathogenic Phenylketonuria 2016-03-18 criteria provided, single submitter clinical testing Variant summary: c.506G>A affects a conserved nucleotide, resulting in amino acid change from Arg to His. 4/5 in-silico tools predict this variant to be damaging. These in silico predictions have not been validated by any in vitro/vivo functional studies yet. This variant was found in 31/117618 control chromosomes at a frequency of 0.0002636, which does not significantly exceed maximal expected frequency of a pathogenic allele (0.0079057). This variant has been reported in multiple mild hyperphenylalaninaemia (MHP) patients with another pathogenic variant on the other allele. One clinical laboratory classified this variant as pathogenic via ClinVar, without evidence to independently evaluate. Taken together, this variant was classified as a probably pathogenic variant until more information becomes available.

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