Submissions for variant NM_000277.3(PAH):c.136G>A (p.Gly46Ser)

gnomAD frequency: 0.00003  dbSNP: rs74603784

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000000661	SCV001250543	pathogenic	Phenylketonuria	2019-12-22	reviewed by expert panel	curation	The PAH variant c.136G>A (p.Gly46Ser) was detected in four alleles associated with moderate PKU (phenylalanine values of 900-1200 micromol/L). Patients included in the study had serum phenylalanine levels above 150 micromol/L and normal urinary excretion of biopterin and neopterin (PMID: 7556322). The variant c.136G>A (p.Gly46Ser) was documented in trans with seven other PAH pathogenic or likely pathogenic variants in 15 Norwegian patients with mild and classic PKU. Haplotype analysis of index cases and parents was conducted, when necessary siblings were also investigated (PMID: 8829656). PM3_Very Strong (14 points). In vitro, enzyme activity assays demonstrated a residual activity for the PAH variant c.136G>A (p.Gly46Ser) between 26% and 38% compared to the wild type PAH when using the mammalian cell-free transcription-translation system (PMID: 11161839). According to gnomAD, this variant is present at a low allele frequency in population databases, with the highest reported frequency in the European (Non-Finnish) population (0.00015). In silico modeling, predictions are conflicting. According to SIFT this variant is predicted to be tolerated, probably damaging by Polyphen 2-HVAR and disease-causing Automatic by Mutation Taster. In summary, this variant meets the criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3_Very Strong, PP4 met_moderate, and PS3.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000000661	SCV000835867	pathogenic	Phenylketonuria	2023-12-10	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 46 of the PAH protein (p.Gly46Ser). This variant is present in population databases (rs74603784, gnomAD 0.02%). This missense change has been observed in individuals with PAH-related conditions (PMID: 7556322, 9634518, 23500595, 26210745). ClinVar contains an entry for this variant (Variation ID: 629). 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 have shown that this missense change affects PAH function (PMID: 8829656, 11326337, 20937381, 21953985, 23500595, 28174686). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000000661	SCV000917930	pathogenic	Phenylketonuria	2018-11-19	criteria provided, single submitter	clinical testing	Variant summary: PAH c.136G>A (p.Gly46Ser) results in a non-conservative amino acid change located in the ACT domain (IPR002912) 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 7.6e-05 in 277146 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in PAH causing Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (7.6e-05 vs 0.0079), allowing no conclusion about variant significance. c.136G>A has been reported in the literature in multiple individuals affected with Phenylalanine Hydroxylase Deficiency (e.g. Bueno_2013, Eiken_1996). These data indicate that the variant is very likely to be associated with disease. Publications also reported experimental evidence evaluating an impact on protein function. The variant effect resulted in a smaller than 30% of normal activity (Bueno_2013, Eiken_1996). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000000661	SCV002813885	pathogenic	Phenylketonuria	2022-01-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002512613	SCV003735011	pathogenic	Inborn genetic diseases	2022-02-07	criteria provided, single submitter	clinical testing	The c.136G>A (p.G46S) alteration is located in exon 2 (coding exon 2) of the PAH gene. This alteration results from a G to A substitution at nucleotide position 136, causing the glycine (G) at amino acid position 46 to be replaced by a serine (S). Based on data from gnomAD, the A allele has an overall frequency of 0.01% (21/282814) total alleles studied. The highest observed frequency was 0.02% (20/129138) of European (non-Finnish) alleles. This alteration has been detected in the homozygous state, and in the compound heterozygous state in conjunction with another pathogenic PAH mutation, in multiple unrelated individuals with phenylalanine hydroxylase (PAH) deficiency (Ferreira, 2021; Aldamiz-Echevarria, 2016; Bueno, 2013; Trunzo, 2015; Couce, 2013; Guldberg, 1993; Guldberg, 1998; Eiken, 1996). In vitro experimental studies show that the G46S alteration impacts protein function (Leandro, 2011; Eiken, 1996; Shi, 2012; Gjetting, 2001; Couce, 2013, Leandro, 2017). Based on the available evidence, this alteration is classified as pathogenic.
Baylor Genetics	RCV000000661	SCV004201379	pathogenic	Phenylketonuria	2024-01-23	criteria provided, single submitter	clinical testing
OMIM	RCV000000661	SCV000020811	pathogenic	Phenylketonuria	1996-01-01	no assertion criteria provided	literature only
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000088836	SCV000119428	not provided	not provided		no assertion provided	not provided
Natera, Inc.	RCV000000661	SCV002088677	pathogenic	Phenylketonuria	2020-10-16	no assertion criteria provided	clinical testing