ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.301G>A (p.Asp101Asn) (rs1555207979)

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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 RCV000669377 SCV001370875 likely pathogenic Phenylketonuria 2020-04-10 reviewed by expert panel curation The c.301G>A (p.Asp101Asn) variant in PAH has been reported in 3 patients with PKU (BH4 deficiency excluded) (PMID: 26503515, 26600521, 28982351). This variant is absent from controls in ExAC, gnomAD, 1000 Genomes, ESP. Conflicting computational evidence: SIFT (T); PolyPhen-2 (B); MutationTaster (D); REVEL=0.465. It is detected in trans with pathogenic variants Q267E and p.Arg158Trp. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3_strong.
Counsyl RCV000669377 SCV000794125 uncertain significance Phenylketonuria 2017-09-14 criteria provided, single submitter clinical testing
Invitae RCV000669377 SCV000936489 pathogenic Phenylketonuria 2018-09-07 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with asparragine at codon 101 of the PAH protein (p.Asp101Asn). The aspartic acid residue is moderately conserved and there is a small physicochemical difference between aspartic acid and asparragine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in combination with another PAH variant in several individuals affected with phenylketonuria (PMID: 28982351). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000669377 SCV001339025 pathogenic Phenylketonuria 2020-03-09 criteria provided, single submitter clinical testing Variant summary: PAH c.301G>A (p.Asp101Asn) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251456 control chromosomes. c.301G>A has been reported in the literature in individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) and HPA (Li_2015, Liu_2017, Wang_2018). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as pathogenic, and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic.

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