ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.1174T>A (p.Phe392Ile)

gnomAD frequency: 0.00007  dbSNP: rs180819807
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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen PAH Variant Curation Expert Panel RCV001058418 SCV001250560 pathogenic Phenylketonuria 2019-10-17 reviewed by expert panel curation This c.1174T>A (p.F392I) variant was documented 19 times in patients with PAH deficiency; DHPR activity, biopterin and/or pteridine analysis was performed to rule out other causes of hyperphenylalaninemia (PMID: 26503515, 30459323, 26322415, 30747360). This variant was detected in at least 8 mild hyperphenylalaninemia (MHP) patients and 1 classical PKU patient with a pathogenic variant in trans (PMID: 24401910, 29316886, 30050108, 31445982). This missense variant is predicted to be damaging (SIFT), probably damaging (PolyPhen2), and disease causing (MutationTaster). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP3, PP4_moderate, PM3_very strong.
Labcorp Genetics (formerly Invitae), Labcorp RCV001058418 SCV001222984 pathogenic Phenylketonuria 2024-02-20 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 392 of the PAH protein (p.Phe392Ile). This variant is present in population databases (rs180819807, gnomAD 0.08%). This missense change has been observed in individual(s) with hyperphenylalaninemia or phenylketonuria (PMID: 24401910, 26322415, 29499199, 30459323, 31102715). ClinVar contains an entry for this variant (Variation ID: 853581). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PAH protein function with a negative predictive value of 80%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on PAH function (PMID: 24401910). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics RCV001058418 SCV002809181 pathogenic Phenylketonuria 2021-10-27 criteria provided, single submitter clinical testing
Revvity Omics, Revvity RCV001058418 SCV003822337 pathogenic Phenylketonuria 2022-11-21 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001058418 SCV003922610 pathogenic Phenylketonuria 2023-03-27 criteria provided, single submitter clinical testing Variant summary: PAH c.1174T>A (p.Phe392Ile) results in a non-conservative amino acid change located in the Aromatic amino acid hydroxylase, C-terminal domain (IPR019774) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.8e-05 in 251308 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in PAH causing Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (6.8e-05 vs 0.0079), allowing no conclusion about variant significance. c.1174T>A has been reported in the literature as bialelic compound heterozygous genotypes in multiple individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (example, Li_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/ascertained. Four clinical diagnostic laboratories and the ClinGen PAH Variant Curation Expert Panel have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics RCV001058418 SCV004201368 pathogenic Phenylketonuria 2024-03-28 criteria provided, single submitter clinical testing
GeneDx RCV004773274 SCV005385264 pathogenic not provided 2024-04-22 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29316886, 24401910, 26322415, 31102715, 26503515, 30050108, 32654453, 31445982, 30459323, 30747360, 29499199, 34653385, 32039316, 35952926, 32778825, 38470552, 32668217, 34394177, 36755623, 35502621, 33980295, 35085585, 32893076, 37004080, 35664874, 35665479, 31737040, 36845377, 36787440, 38380423, 37098607, 36104584, 33058845)
Juno Genomics, Hangzhou Juno Genomics, Inc RCV001058418 SCV005417814 pathogenic Phenylketonuria criteria provided, single submitter clinical testing PM3_VeryStrong+PP4+PP3
Natera, Inc. RCV001058418 SCV002088625 pathogenic Phenylketonuria 2020-12-04 no assertion criteria provided clinical testing
Neonatal Disease Screening Center, Medical Genetics Center, Huaihua City Maternal and Child Health Care Hospital RCV001058418 SCV004800861 likely pathogenic Phenylketonuria no assertion criteria provided clinical testing PM3_VS+PP1+PP3+PP4_M
PreventionGenetics, part of Exact Sciences RCV004740552 SCV005359942 pathogenic PAH-related disorder 2024-09-18 no assertion criteria provided clinical testing The PAH c.1174T>A variant is predicted to result in the amino acid substitution p.Phe392Ile. This variant has been reported multiple times in patients with phenylalanine hydroxylase deficiency, with most patients presenting with mild hyperphenylalaninemia (e.g., Chen et al. 2018. PubMed ID: 30459323; Tao et al. 2015. PubMed ID: 26322415; Additional File 1 in Liu et al. 2017. PubMed ID: 28982351; Table S1 in Li et al. 2018. PubMed ID: 30050108; Yan et al. 2019. PubMed ID: 30747360). This variant is reported in 0.092% of alleles in individuals of East Asian descent in gnomAD. This variant is interpreted as pathogenic in ClinVar, including by the ClinGen PAH Variant Curation Expert Panel (https://www.ncbi.nlm.nih.gov/clinvar/variation/853581/). In summary, this variant is interpreted as pathogenic.

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