ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.809G>A (p.Arg270Lys) (rs62514950)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen PAH Variant Curation Expert Panel RCV000153632 SCV001370805 pathogenic Phenylketonuria 2020-06-08 reviewed by expert panel curation The c.809G>A (p.Arg270Lys) variant in PAH has been reported in multiple individuals with PAH deficiency (BH4 deficiency excluded). (PMID: 21871829, 23856132). This variant has an extremely low allele frequency (MAF=0.00016) in gnomAD. This variant has 11% residual PAH activity (PMID: 27620137). This variant was detected with multiple pathogenic variants: IVS10nt-11G>A (2 patients), L348V, S349P, R158Q, E390G, D415N (PMID: 21871829); and IVS4+5G>T (PMID: 23856132). Computational prediction tools and conservation analysis support a deleterious effect. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_very-strong, PM2, PP4_Moderate, PP3, PS3_supporting.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000089105 SCV000203180 pathogenic not provided 2014-01-15 criteria provided, single submitter clinical testing
Invitae RCV000153632 SCV000629217 pathogenic Phenylketonuria 2019-09-13 criteria provided, single submitter clinical testing This sequence change replaces arginine with lysine at codon 270 of the PAH protein (p.Arg270Lys). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and lysine. This variant is present in population databases (rs62514950, ExAC 0.009%). This variant has been reported as homozygous in an individual affected with phenylketonuria (PMID: 23856132) or in combination with other deleterious PAH variants in individuals affected with phenylketonuria and hyperphenylalaninemia (PMID: 23500595, 12173030, 20187763, 23856132, 20082265). ClinVar contains an entry for this variant (Variation ID: 102846). Experimental studies have shown that this missense change significantly reduces phenylalanine binding, PAH enzyme activity and affects the protein's stability in vitro (PMID: 17935162, 27620137, 16545551, 25453233). For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000153632 SCV000696467 pathogenic Phenylketonuria 2017-07-05 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000089105 SCV001249179 pathogenic not provided 2019-02-01 criteria provided, single submitter clinical testing
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000089105 SCV000119712 not provided not provided no assertion provided not provided

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