Submissions for variant NM_000277.3(PAH):c.755G>A (p.Arg252Gln)

gnomAD frequency: 0.00001  dbSNP: rs62644503

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000179742	SCV000852163	pathogenic	Phenylketonuria	2018-08-10	reviewed by expert panel	curation	PAH-specific ACMG/AMP criteria applied: PM2: ; PP3: tools predict damaging; PS3: BioPKU 3% enzyme activity; 3.8% residual activity (PMID:24401910); PM3: Detected in trans with p.Pro407fs (PMID:7833954); PP4_Moderate: Detected in 2 patients with classic PKU (Phe>1.5mM). BH4 deficiency excluded (PMID:7833954; PMID:9634518). In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM2, PP3, PS3, PM3, PP4_Moderate).
Eurofins Ntd Llc (ga)	RCV000089080	SCV000232039	pathogenic	not provided	2015-04-28	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000089080	SCV000601717	pathogenic	not provided	2021-04-27	criteria provided, single submitter	clinical testing	The variant is associated with classic PKU in the published literature (PMID: 9634518 (1998), 24401910 (2014)). Assessment of experimental evidence regarding the effect of this variant suggests it disrupts normal PAH enzymatic activity (PMID: 24401910 (2014), 21953985 (2012), 11243094 (1997)). Therefore, the variant is classified as pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000179742	SCV000893944	pathogenic	Phenylketonuria	2018-10-31	criteria provided, single submitter	clinical testing
Invitae	RCV000179742	SCV000944724	pathogenic	Phenylketonuria	2023-11-27	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 252 of the PAH protein (p.Arg252Gln). This variant is present in population databases (rs62644503, gnomAD 0.005%). This missense change has been observed in individuals with phenylketonuria (PMID: 7833954, 16256386, 23430547, 24401910, 30050108). ClinVar contains an entry for this variant (Variation ID: 102824). 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 expected to disrupt PAH protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects PAH function (PMID: 11243094, 17924342, 21953985). This variant disrupts the p.Arg252 amino acid residue in PAH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 2574153, 8116675, 12655546, 17096675, 20082265, 25596310). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000179742	SCV001361334	pathogenic	Phenylketonuria	2019-12-09	criteria provided, single submitter	clinical testing	Variant summary: PAH c.755G>A (p.Arg252Gln) results in a conservative amino acid change located in the aromatic amino acid hydroxylase, C-terminal domain (IPR019774) 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 8e-06 in 251262 control chromosomes. c.755G>A has been reported in the literature in multiple individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (example, Benit_1994, Liang_2014, Li_2018). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in categorization as a functionally hemizygous variant with less than 10% of normal activity (Li_2018). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
3billion	RCV000179742	SCV002573148	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: 0.001%). 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. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 24401910). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.94; 3Cnet: 0.99). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 7833954). Different missense changes at the same codon (p.Arg252Gly, p.Arg252Pro, p.Arg252Trp) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000000584 , VCV000102823 , VCV000932252). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
GeneDx	RCV000089080	SCV002576977	pathogenic	not provided	2022-09-28	criteria provided, single submitter	clinical testing	Reported in an individual with PKU who harbored a second PAH variant (Benit et al., 1994); Functional analysis demonstrates decreased PAH enzyme activity (Liang et al., 2014); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 21228398, 30747360, 21953985, 7833954, 8188310, 24401910, 27264808, 9634518, 11243094, 30037505, 30275481, 34426522, 31589614, 32668217, 32778825)
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000179742	SCV003920888	likely pathogenic	Phenylketonuria	2021-03-30	criteria provided, single submitter	clinical testing	PAH NM_000277.2 exon 7 p.Arg252Gln (c.755G>A): This variant has been reported in the literature as a compound heterozygote in at least 1 individual with PKU (Benit 1994 PMID:7833954) and has been reported in the BIOPKU database (http://www.biopku.org). This variant is present in 0.005% (1/19948) of East Asian alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/12-103246680-C-T). Please note, disease causing variants may be present in control databases at low frequencies, reflective of the general population, carrier status and/or variable expressivity. This variant is present in ClinVar (Variation ID:102824). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. Of note, computational tools designed to predict splicing suggest a potential effect from this variant. However, further studies are needed to understand its impact. Functional studies support a deleterious effect of this variant, suggesting decreased protein production or activity compared to wild-type (Bjorgo 1998 PMID:9799096, Shi 2012 PMID:21953985, Himmelreich 2018 PMID:30037505). Furthermore, other variants at this same codon (p.Arg252Pro, p.Arg252Trp, p.Arg252Gly) have been reported in the literature, with at least one of these variants with sufficient evidence for association with disease. In summary, data on this variant is highly suspicious for disease, but requires further evidence for pathogenicity. Therefore, this variant is classified as likely pathogenic.
Baylor Genetics	RCV000179742	SCV004201363	pathogenic	Phenylketonuria	2024-03-01	criteria provided, single submitter	clinical testing
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000089080	SCV000119686	not provided	not provided		no assertion provided	not provided
Natera, Inc.	RCV000179742	SCV001453107	pathogenic	Phenylketonuria	2020-09-16	no assertion criteria provided	clinical testing