Submissions for variant NM_000277.3(PAH):c.527G>A (p.Arg176Gln)

dbSNP: rs74486803

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000810165	SCV001448614	pathogenic	Phenylketonuria	2020-10-15	reviewed by expert panel	curation	This c.527G>A (p.Arg176Gln) variant in PAH was reported in at least two patients with PAH deficiency (PMID: 30459323, 26210745, and 27121329) and detected with pathogenic variants p.Val388Met, p.Arg158Gln, and Arg243Gln (PMID: 27121329,10234516, and 30459323). This variant has extremely low frequency in gnomAD (MAF=0.00007). One other missense variant at this amino acid residue is determined to be pathogenic in ClinVar: p.Arg176Leu by nine submitters. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific AMCG/AMP criteria applied: PM3_strong, PM2, PM5, and PP4_moderate.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000810165	SCV000950356	pathogenic	Phenylketonuria	2024-10-23	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 176 of the PAH protein (p.Arg176Gln). This variant is present in population databases (rs74486803, gnomAD 0.006%). This missense change has been observed in individuals with hyperphenylalaninemia (PMID: 10234516, 23500595, 26210745, 27121329, 30459323). ClinVar contains an entry for this variant (Variation ID: 102724). 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.Arg176 amino acid residue in PAH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8088845, 23500595, 27121329). 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.
Myriad Genetics, Inc.	RCV000810165	SCV002060094	likely pathogenic	Phenylketonuria	2021-11-10	criteria provided, single submitter	clinical testing	NM_000277.1(PAH):c.527G>A(R176Q) is a missense variant classified as likely pathogenic in the context of phenylalanine hydroxylase deficiency. The R176Q variant can be associated with variant or non-PKU hyperphenylalaninemia. R176Q has been observed in cases with relevant disease (PMID: 10234516, 29499199, 26210745, 30459323, 27121329, Gundorova_2017_(no PMID; article), Tao_2019_(no PMID; poster), 32668217). Functional assessments of this variant are not available in the literature. R176Q has been observed in population frequency databases (gnomAD: SAS 0.01%). In summary, NM_000277.1(PAH):c.527G>A(R176Q) is a missense variant that has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
3billion, Medical Genetics	RCV000810165	SCV002572654	pathogenic	Phenylketonuria	2022-09-01	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.003%). It is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.62; 3Cnet: 0.51). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000102724). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals (PMID: 10234516 , 27121329 , 30459323). Different missense changes at the same codon (p.Arg176Leu, p.Arg176Pro) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000000631 , VCV000102725). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Baylor Genetics	RCV000810165	SCV004201326	likely pathogenic	Phenylketonuria	2024-03-18	criteria provided, single submitter	clinical testing
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000088972	SCV000119575	not provided	not provided		no assertion provided	not provided
Natera, Inc.	RCV000810165	SCV001455096	pathogenic	Phenylketonuria	2020-09-16	no assertion criteria provided	clinical testing