Submissions for variant NM_000277.3(PAH):c.1157A>G (p.Tyr386Cys)

gnomAD frequency: 0.00003  dbSNP: rs62516141

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000169306	SCV002032214	pathogenic	Phenylketonuria	2021-05-15	reviewed by expert panel	curation	The c.1157A>G (p.Tyr386Cys) variant in PAH has been reported in multiple probands with PKU (BH4 deficiency excluded) (PMID: 16198137; PP4_Moderate). This variant has been detected with c.1315+1G>A, R252W, L311P, R261Q, I65V, Q178G, R158Q (all reported as Pathogenic in ClinVar, 4.0 points total) (PMIDs:24368688, 24941924, 22841515, 16198137, 26210745, 23357515, 18493213; PM3_very-strong). This variant is absent from population databases (PM2) and is predicted deleterious by SIFT, PolyPhen2, MutationTaster, and REVEL = 0.975 (PP3). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_very-strong, PM2, PP4_Moderate, PP3.
Counsyl	RCV000169306	SCV000220627	likely pathogenic	Phenylketonuria	2014-08-22	criteria provided, single submitter	literature only
GeneDx	RCV000088771	SCV000239087	pathogenic	not provided	2024-08-16	criteria provided, single submitter	clinical testing	Reported previously in association with hyperphenylalaninemia and seen in patients with classic PKU in the presence of another pathogenic variant (PMID: 8533759, 26210745, 24941924); Not observed at significant frequency in large population cohorts (gnomAD); 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: 24941924, 24350308, 16765994, 22841515, 17924342, 29499199, 25087612, 11385716, 23357515, 11696894, 8533759, 24368688, 23430918, 12655553, 23074961, 10394930, 9634518, 18493213, 16198137, 32668217, 35405047, 36646061, 36537053, 21445337, 34828281, 26210745)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000169306	SCV000754086	pathogenic	Phenylketonuria	2025-01-12	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 386 of the PAH protein (p.Tyr386Cys). This variant is present in population databases (rs62516141, gnomAD 0.004%). This missense change has been observed in individual(s) with phenylketonuria or hyperphenylalaninemia (PMID: 16198137, 16765994, 22841515, 23430918, 24350308, 24368688). ClinVar contains an entry for this variant (Variation ID: 102538). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt PAH protein function with a positive predictive value of 80%. This variant disrupts the p.Tyr386 amino acid residue in PAH. Other variant(s) that disrupt this residue have been observed in individuals with PAH-related conditions (PMID: 23430918), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000169306	SCV000917928	pathogenic	Phenylketonuria	2018-10-26	criteria provided, single submitter	clinical testing	Variant summary: PAH c.1157A>G (p.Tyr386Cys) results in a non-conservative amino acid change located in the Aromatic amino acid hydroxylase, C-terminal domain (IPR019774) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 246044 control chromosomes (gnomAD). c.1157A>G has been reported in the literature in multiple individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria)(Bayat_2016, Trunzo_2015, Ho_2014). 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 ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV000169306	SCV004209590	pathogenic	Phenylketonuria	2023-12-13	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000088771	SCV005414103	pathogenic	not provided	2023-11-03	criteria provided, single submitter	clinical testing	PP3, PM2_moderate, PM3_very_strong, PS4_moderate
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000088771	SCV005624689	pathogenic	not provided	2024-05-10	criteria provided, single submitter	clinical testing	The PAH c.1157A>G (p.Tyr386Cys) variant has been reported in the published literature in multiple individuals affected with phenylketonuria (PKU) (PMID: 8533759 (1995), 10394930 (1999), 11385716 (2001), 12655553 (2003), 16198137 (2005), 16765994 (2006), 18493213 (2008), 22841515 (2012), 23357515 (2013), 23430918 (2012), 24350308 (2013), 24368688 (2014), 24941924 (2015), 26210745 (2015), 34828281 (2021), 36537053 (2022)). The frequency of this variant in the general population, 0.000044 (5/113648 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as pathogenic.
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000088771	SCV000119356	not provided	not provided		no assertion provided	not provided
Natera, Inc.	RCV000169306	SCV002088626	pathogenic	Phenylketonuria	2020-10-14	no assertion criteria provided	clinical testing
Undiagnosed Diseases Network, NIH	RCV003162523	SCV003915641	pathogenic	Polymicrogyria, perisylvian, with cerebellar hypoplasia and arthrogryposis	2022-10-27	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004739362	SCV005362567	pathogenic	PAH-related disorder	2024-08-19	no assertion criteria provided	clinical testing	The PAH c.1157A>G variant is predicted to result in the amino acid substitution p.Tyr386Cys. This variant has been reported, in the homozygous state or with a second causative PAH variant, in multiple individuals with phenylalanine hydroxylase deficiency (e.g., Fiori et al. 2005. PubMed ID: 16198137; Lüleyap et al. 2006. PubMed ID: 16765994; Quirk et al. 2012. PubMed ID: 22841515; Sarkissian et al. 2012. PubMed ID: 23430918; Table S3, Hillert et al. 2020. PubMed ID: 32668217). We have also observed this variant in presumably affected individuals that also carried a second pathogenic or likely pathogenic variant in PAH (PreventionGenetics internal data). This variant is interpreted as pathogenic by the ClinGen PAH Variant Curation Expert Panel, and as likely pathogenic or pathogenic by other submitters to ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/102538). This variant is reported in 0.0044% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Based on the collective evidence, we classify this variant as pathogenic.