ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.212G>A (p.Arg71His) (rs62508695)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen PAH Variant Curation Expert Panel RCV000672919 SCV001146695 likely pathogenic Phenylketonuria 2019-09-29 reviewed by expert panel curation The c.212G>A (p.Arg71His) variant in PAH has been reported in multiple individual with PAH deficiency with BH4 deficiency excluded (PP4_Moderate; PMID: 10495930, 26503515). This variant is absent in population databases (PM2). This variant was detected in trans with known pathogenic variant p.R408W (PM3). Computational evidence supports a deleterious effect. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3, PP3.
GeneDx RCV000088876 SCV000239046 likely pathogenic not provided 2018-03-05 criteria provided, single submitter clinical testing The R71H variant in the PAH gene has been reported previously in a patient with mild hyperphenylalaninemia who was heterozygous for the R71H variant and another variant (Zekanowski et al., 1999). The R71H variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R71H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is not conserved. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in the same and multiple nearby residues (E66K, S67P, R68G, R68S, P69S, S70P, S70F, E76K, E76A, E76, E76D) have been reported in the Human Gene Mutation Database in association with phenylketonuria or hyperphenylalaninemia (Stenson et al., 2014), supporting the functional importance of this region of the protein. The R71H variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded.
Counsyl RCV000672919 SCV000798074 uncertain significance Phenylketonuria 2018-02-21 criteria provided, single submitter clinical testing
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000088876 SCV000119473 not provided not provided no assertion provided not provided

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