ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.320A>G (p.His107Arg) (rs542645236)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen PAH Variant Curation Expert Panel RCV000210807 SCV001572860 pathogenic Phenylketonuria 2020-12-09 reviewed by expert panel curation This c.320A>G (p.His107Arg) variant in PAH was reported in 22 patients with PAH deficiency (>120 uMol/L Phe), detected in trans in 16 patients with pathogenic variants p.Arg111*, p.Arg400Thr, p.Val399=, p.Val399=, p.Arg241Cys, p.Arg241Cys, p.Arg413Pro, p.Gly257Val, p.His107Arg, p.Arg243Gln, p.His220Pro, p.Arg176*, p.Arg243Gln, p.Arg243Gln, p.Val230Ile, p.Ile65Thr (PMID: 28982351). Computational evidence for this variant is conflicting; predicted to be tolerated (SIFT), disease-causing (MutationTaster) and benign (PolyPhen2). This variant is present in European (Non-Finnish) populations at extremely low frequencies in gnomAD (MAF=0.00002), ExAC (MAF=0.00001), and 1000 Genomes (MAF=0.00099). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3_very-strong, PP4.
Counsyl RCV000210807 SCV000791589 likely pathogenic Phenylketonuria 2017-05-13 criteria provided, single submitter clinical testing
Baylor Genetics RCV000210807 SCV001163352 pathogenic Phenylketonuria criteria provided, single submitter clinical testing
Invitae RCV000210807 SCV001223781 pathogenic Phenylketonuria 2020-08-25 criteria provided, single submitter clinical testing This sequence change replaces histidine with arginine at codon 107 of the PAH protein (p.His107Arg). The histidine residue is highly conserved and there is a small physicochemical difference between histidine and arginine. This variant is present in population databases (rs542645236, ExAC 0.001%). This variant has been observed in individuals with PAH-related disease (PMID: 26600521, 30050108, 25456745, 29390883, 21307867). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 225134). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic.
Department of Prenatal Diagnosis, Women’s Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care Hospital RCV000210807 SCV000266851 likely pathogenic Phenylketonuria 2013-10-01 no assertion criteria provided clinical testing

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