ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.136G>A (p.Gly46Ser) (rs74603784)

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Total submissions: 5
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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.
Invitae RCV000000661 SCV000835867 pathogenic Phenylketonuria 2019-07-09 criteria provided, single submitter clinical testing This sequence change replaces glycine with serine at codon 46 of the PAH protein (p.Gly46Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. This variant is present in population databases (rs74603784, ExAC 0.02%). This variant has been reported in multiple individuals affected with PAH-related disease (PMID: 23500595, 7556322, 26210745) and associated with both mild and classic PKU phenotypes (PMID: 9634518, 23500595). ClinVar contains an entry for this variant (Variation ID: 629). Experimental studies have shown that this missense change impairs the function of the encoded protein in vitro (PMID: 20937381, 8829656, 21953985, 11326337, 23500595, 28174686). For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America 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.
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

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