ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.280A>G (p.Ile94Val)

gnomAD frequency: 0.00010  dbSNP: rs528078207
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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 RCV001114785 SCV001448613 uncertain significance Phenylketonuria 2020-10-15 reviewed by expert panel curation This c.280A>G (p.Ile94Val) variant in PAH was reported in at least three patients with PAH deficiency. BH4 deficiency was ruled out through a BH4 loading test, a urinary pterin analysis, and a DHPR activity assay in at least one case (PMID: 30747360, 30459323, and 28982351). This variant is present in the East Asian at a frequency of 0.00160, higher than the PAH Variant Curation Expert Panel cutoff of 0.0002. Computational evidence is conflicting in the predicted effect of this variant. In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PP4_moderate.
Illumina Laboratory Services, Illumina RCV001114785 SCV001272693 uncertain significance Phenylketonuria 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Fulgent Genetics, Fulgent Genetics RCV001114785 SCV002775201 uncertain significance Phenylketonuria 2022-02-03 criteria provided, single submitter clinical testing
Invitae RCV001114785 SCV003270640 uncertain significance Phenylketonuria 2022-07-05 criteria provided, single submitter clinical testing This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 94 of the PAH protein (p.Ile94Val). This variant is present in population databases (rs528078207, gnomAD 0.2%). This missense change has been observed in individual(s) with clinical features of hyperphenylalaninemia (PMID: 28982351). ClinVar contains an entry for this variant (Variation ID: 883981). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003226435 SCV003922614 uncertain significance not specified 2023-03-27 criteria provided, single submitter clinical testing Variant summary: PAH c.280A>G (p.Ile94Val) results in a conservative amino acid change located in the ACT domain (IPR002912) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00012 in 251440 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in PAH causing Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (0.00012 vs 0.0079), allowing no conclusion about variant significance. c.280A>G has been reported in the literature in individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (example, PMID: 30459323, 28982351, 30747360). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories and the ClinGen PAH Variant Curation Expert Panel have submitted clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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