Submissions for variant NM_000277.3(PAH):c.261C>A (p.Ser87Arg)

gnomAD frequency: 0.00004  dbSNP: rs62516151

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000000613	SCV000696445	pathogenic	Hyperphenylalaninemia	2017-08-07	criteria provided, single submitter	clinical testing	Variant summary: The PAH c.261C>A (p.Ser87Arg) variant involves the alteration of a non-conserved nucleotide and 2/4 in silico tools (MutationTaster not captured here due to low p-value) predict a damaging outcome. This variant was found in 10/121410 control chromosomes at a frequency of 0.0000824, which does not exceed the estimated maximal expected allele frequency of a pathogenic PAH variant (0.0079057). The variant of interest has been reported in affected individuals via publication, predominantly showing a mild HPA phenotype. In addition, a clinical diagnostic laboratory and reputable database classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000763293	SCV000893954	likely pathogenic	Phenylketonuria	2018-10-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000763293	SCV000914558	pathogenic	Phenylketonuria	2018-08-14	criteria provided, single submitter	clinical testing	The PAH c.261C>A (p.Ser87Arg) missense variant has been reported in a compound heterozygous state in six unrelated individuals with phenylalanine hydroxylase deficiency, including in five with mild hyperphenylalaninemia and in one with mild phenylketonuria (Guldberg et al. 1994; Zekanowski et al. 1999; Desviat et al. 2004; Bueno et al. 2013; Ohlsson et al. 2017). The p.Ser87Arg variant was also identified in at least one additional individual, but the zygosity of the variant was not provided (Zurflüh et al. 2008; Couce et al. 2013). The variant was absent from 220 control chromosomes, but is reported at a frequency of 0.00014 in the European (non-Finnish) population of the Exome Aggregation Consortium. In addition, Couce et al. (2013) report data from the PAHdb which indicates in vitro residual PAH activity at 25-82% of wild type for the variant. Based on the evidence, the p.Ser87Arg variant is classified as pathogenic for phenylalanine hydroxylase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000763293	SCV001218411	pathogenic	Phenylketonuria	2025-01-08	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 87 of the PAH protein (p.Ser87Arg). This variant is present in population databases (rs62516151, gnomAD 0.01%). This missense change has been observed in individual(s) with hyperphenylalaninemia (PMID: 8088845, 10495930). ClinVar contains an entry for this variant (Variation ID: 583). 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%. Experimental studies have shown that this missense change affects PAH function (PMID: 23500595). For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity	RCV000763293	SCV002020219	likely pathogenic	Phenylketonuria	2019-12-24	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002512609	SCV003708772	pathogenic	Inborn genetic diseases	2021-01-26	criteria provided, single submitter	clinical testing	The c.261C>A (p.S87R) alteration is located in coding exon 3 of the PAH gene. This alteration results from a C to A substitution at nucleotide position 261, causing the serine (S) at amino acid position 87 to be replaced by an arginine (R). Based on data from the Genome Aggregation Database (gnomAD), the PAH c.261C>A alteration was not observed, with coverage at this position. The c.261C>A (p.S87R) alteration has been reported in combination with a second pathogenic alteration in multiple unrelated families presenting with hyperphenylalaninemia and mild PKU (Bueno, 2013; Desviat, 2004; Guldberg, 1993; Jeannesson-Thivisol, 2015; Rajabi, 2019). The p.S87 amino acid is not conserved in available vertebrate species. The in silico prediction for the p.S87R alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic.
Baylor Genetics	RCV000763293	SCV004209596	pathogenic	Phenylketonuria	2024-03-25	criteria provided, single submitter	clinical testing
OMIM	RCV000000613	SCV000020763	pathogenic	Hyperphenylalaninemia	1994-05-15	no assertion criteria provided	literature only
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000088884	SCV000119481	not provided	not provided		no assertion provided	not provided
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000088884	SCV001742956	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000088884	SCV001975092	pathogenic	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003934787	SCV004754012	pathogenic	PAH-related disorder	2024-03-07	no assertion criteria provided	clinical testing	The PAH c.261C>A variant is predicted to result in the amino acid substitution p.Ser87Arg. This variant has been reported along with a second causative PAH variant in multiple patients with phenylalanine hydroxylase deficiency (Guldberg et al. 1994. PubMed ID: 8088845; Zekanowski et al. 1999. PubMed ID: 10495930; Desviat et al. 2004. PubMed ID: 15464430; Jeannesson-Thivisol et al. 2015. PubMed ID: 26666653; Table S3, Hillert A et al 2020. PubMed ID: 32668217). This variant has been reported to be associated with mild hyperphenylalaninemia (Table S2, Hillert A et al 2020. PubMed ID: 32668217). Internally, we have observed this variant along with a second causative PAH variant in patients with abnormal newborn screen results suggestive of phenylalanine hydroxylase deficiency. The p.Ser87 amino acid resides in the PAH regulatory domain, and in functional studies the p.Ser87Arg substitution has been reported to reduce activity of the PAH enzyme to between ~25-82% of wild-type (Gjetting et al. 2001. PubMed ID: 11161839; Couce et al. 2013. PubMed ID: 23500595). The p.Ser87Arg substitution has been reported to result in a PAH enzyme that is responsive to tetrahydrobiopterin (BH4) (Zurflüh et al. 2008. PubMed ID: 17935162). A different nucleotide change leading to the same amino acid substitution (c.259A>C, p.Ser87Arg) has also been reported in association with phenylalanine hydroxylase deficiency (Himmelreich et al. 2018. PubMed ID: 30037505). The c.261C>A (p.Ser87Arg) variant is reported in 0.013% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Based on these observations, this variant is interpreted as pathogenic.