ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.505C>G (p.Arg169Gly)

dbSNP: rs281865440
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen PAH Variant Curation Expert Panel RCV000666071 SCV001572855 pathogenic Phenylketonuria 2021-02-12 reviewed by expert panel curation The variant c.505C>G (p.R169G) in PAH has been detected in 2 Chinese patients and 1 Dutch patient with Phe levels >120 umol/l (PMID 26503515, 30050108, 31924462) (PP4-Moderate). This variant was detected in trans with pathogenic variants p.R243Q, p.R241Pfs*100; the validation tests on parents were performed using Sanger sequencing. Also found with pathogenic variant p.Y414C; parental testing not confirmed (PMID: 30050108, 31924462) (PM3-Strong). This variant is absent from controls in gnomAD, 1000 Genomes or ESP (PM2). Multiple lines of computational evidence support a deleterious effect: SIFT, PolyPhen2, and MutationTaster. REVEL score =0.848 (PP4). Missesense variant p.Arg169Ser interpreted as pathogenic by ClinGen PAH VCEP, located at the same amino acid residue (PM5). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PP4-Moderate, PM3-Strong, PP3, PM5.
Counsyl RCV000666071 SCV000790309 uncertain significance Phenylketonuria 2017-03-10 criteria provided, single submitter clinical testing

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