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

gnomAD frequency: 0.00007  dbSNP: rs180819807

Total submissions: 11

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.