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

gnomAD frequency: 0.00010  dbSNP: rs528078207

Total submissions: 6

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
Labcorp Genetics (formerly Invitae), Labcorp	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	2024-09-09	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 (gnomAD). 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, 38105685). These data, however do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 28982351, 30747360, 30459323, 35339094, 32668217, 34426522, 38105685). ClinVar contains an entry for this variant (Variation ID: 883981). Based on the evidence outlined above, the variant was classified as uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV004740571	SCV005351455	uncertain significance	PAH-related disorder	2024-07-05	no assertion criteria provided	clinical testing	The PAH c.280A>G variant is predicted to result in the amino acid substitution p.Ile94Val. This variant has been reported in individuals with phenylketonuria or mild hyperphenylalaninemia (Liu et al. 2017. PubMed ID: 28982351; Chen et al. 2018. PubMed ID: 30459323; Yan et al. 2019. PubMed ID: 30747360), and a different amino acid change (p.Ile94Ser) was reported in an individual with phenylketonuria (Guldberg et al. 1998. PubMed ID: 9634518). This variant is reported in 0.16% of alleles in individuals of East Asian descent in gnomAD. This variant was curated by the ClinVar expert PAH panel to be of uncertain significance due to both conflicting computational predictions regarding its pathogenicity and to the fact that its population minor allele frequency is higher than the established pathogenicity cutoff of 0.02% (Zastrow et al. 2018. PubMed ID: 30311390). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.