Submissions for variant NM_000277.3(PAH):c.545A>G (p.Glu182Gly)

gnomAD frequency: 0.00001  dbSNP: rs199475617

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV001248714	SCV001448664	likely pathogenic	Phenylketonuria	2020-07-25	reviewed by expert panel	curation	The NM_000277.3:c.545A>G (p.Glu182Gly) variant is a missense variant in exon 6/13 of PAH. The variant was reported in confirmed trans with the p.R261Q allele (Pathogenic per ClinGen PAH VCEP) among two siblings with mild hyperphenylalanemia; BH4 deficiency was not noted to have been formally excluded (PMID: 26542770) (PP1; PM3). The variant has also been previously reported among “two alleles” in a cohort of Armenian PKU patients among whom BH4 deficiency was excluded; no further detail appears to be given (PMID: 10541324) (PP4_Moderate). It has also been noted in ClinVar (ID 102731), without a classification. Three heterozygotes and zero homozygotes for the variant are present in gnomAD, corresponding to a global AF of 0.0000119 and maximum population frequency of 0.0000264 (non-Finnish European population), under the frequency cutoff of 0.0002 for use of PM2 (PM2). The variant is predicted damaging by multiple in-silico missense predictors, including REVEL (REVEL score 0.929) (PP3). Classification: Likely Pathogenic Supporting Criteria: PM2; PM3; PP1; PP4_Moderate; PP3
Labcorp Genetics (formerly Invitae), Labcorp	RCV001248714	SCV001422220	pathogenic	Phenylketonuria	2024-11-19	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 182 of the PAH protein (p.Glu182Gly). This variant is present in population databases (rs199475617, gnomAD 0.0009%). This missense change has been observed in individual(s) with phenylketonuria (PMID: 26542770). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 102731). 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 not expected to disrupt PAH protein function with a negative predictive value of 80%. This variant disrupts the p.Glu182 amino acid residue in PAH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 31355225). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV001248714	SCV004201958	likely pathogenic	Phenylketonuria	2022-11-16	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV001248714	SCV004848852	likely pathogenic	Phenylketonuria	2022-11-03	criteria provided, single submitter	clinical testing	The p.Glu182Gly variant in PAH has been reported in at least 2 siblings with mild Hyperphenylalaninemia in the compound heterozygous state (Bayat 2016 PMID: 26542770). This variant was classified as Likely Pathogenic on July 25, 2020 by the ClinGen-approved ClinGen PAH Variant Curation Expert Panel (Variation ID 102731) and was absent from large population studies. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Another variant involving this codon (p.Glu182Lys) has been identified in individuals with Phenylketonuria and is classified as pathogenic by a clinical laboratory in ClinVar. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive hyperphenylalanemia/phenylkenonuria. ACMG/AMP Criteria applied: PM2_Supporting, PP3, PM3, PM5.
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000088980	SCV000119584	not provided	not provided		no assertion provided	not provided