Submissions for variant NM_000277.3(PAH):c.1169A>G (p.Glu390Gly)

gnomAD frequency: 0.00008  dbSNP: rs5030856

Total submissions: 22

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000000657	SCV000852141	pathogenic	Phenylketonuria	2018-10-01	reviewed by expert panel	curation	The c.1169A>G (p.Glu390Gly) variant in PAH has been reported on at least 47 alleles, most often with Mild Hyperphenylalaninemia. (BH4 deficiency excluded). (PP4_Moderate; PMID: 8088845; PMID: 21147011). This variant has an extremely low allele frequency (MAF=0.00018 in gnomAD) (PM2; http://gnomAD.broadinstitute.org). This variant was detected in trans with IVS-12nt1, L333F (Pathogenic in ClinVar) + 8 homozygotes (PM3_Very-strong; PMID: 10479481; PMID: 21147011; PMID: 8088845). Computational prediction tools and conservation analysis suggest that the c.1169A>G variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM3_Very-strong
Eurofins Ntd Llc (ga)	RCV000078503	SCV000110359	pathogenic	not provided	2013-09-27	criteria provided, single submitter	clinical testing
GeneDx	RCV000078503	SCV000239089	pathogenic	not provided	2023-10-10	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Classified as being a tetrahydrobiopterin (BH4) responsive variant (PMID: 17935162, 23559577); This variant is associated with the following publications: (PMID: 10472529, 25750018, 23500595, 34828281, 31355225, 26666653, 30963030, 21147011, 22763404, 25087612, 8088845, 11914042, 25596310, 8098245, 28676969, 24048906, 22300847, 15557004, 26803807, 10479481, 31589614, 34426522, 33375644, 32778825, 33465300, 29288420, 23792259, 23559577, 35355500, 36537053, 35328070, 35339094, 35405047, 17935162)
Counsyl	RCV000000657	SCV000485344	likely pathogenic	Phenylketonuria	2016-01-22	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000000656	SCV000696428	pathogenic	Hyperphenylalaninemia	2017-01-03	criteria provided, single submitter	clinical testing	Variant summary: The PAH c.1169A>G (p.Glu390Gly) variant involves the alteration of a conserved nucleotide, present in catalytic domain of the protein (Couce_2013) and is predicted to be damaging by 5/5 in silico tools. This variant was found in 12/121202 control chromosomes at a frequency of 0.000099, which does not exceed the estimated maximal expected allele frequency of a pathogenic PAH variant (0.0079057). This variant is widely described as one of the frequent pathogenic variants that causes hyperphenylalaninemia with consistent genotype-phenotype data and functional studies. Eight homozygotes with this variant were responsive to BH4 (Dobrowolski_2011) which can be attributed to mild functional effect of this variant. Multiple clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant is classified as Pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000000657	SCV000754075	pathogenic	Phenylketonuria	2025-01-14	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 390 of the PAH protein (p.Glu390Gly). This variant is present in population databases (rs5030856, gnomAD 0.02%). This missense change has been observed in individual(s) with mild hyperphenylalaninemia and mild phenylketonuria (PMID: 8088845, 10472529, 10479481, 12655552, 17935162, 21147011, 21871829, 25596310, 26803807). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 625). 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: 17935162, 22300847, 26803807). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000000657	SCV000893266	pathogenic	Phenylketonuria	2022-04-20	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000000657	SCV000914554	pathogenic	Phenylketonuria	2018-08-14	criteria provided, single submitter	clinical testing	Across a selection of the available literature, the PAH c.1169A>G (p.Glu390Gly) missense variant has been identified in a compound heterozygous state in three individuals with phenylalanine hydroxylase deficiency and in one child with non-PKU hyperphenylalaninemia identified by newborn screening and in three individuals with mild hyperhpenylalaninemila. The variant was also identified in 23/630 alleles of individuals with BH4-responsive mild hyperhpenylalaninemila (Guldberg et al. 1994; Zurflüh et al. 2008; Couce et al. 2013; Trunzo et al. 2013). The p.Glu390Gly variant was absent from 110 controls and is reported at a frequency of 0.00018 in the European (non-Finnish) population of the Genome Aggregation Database. Averaged across different cell systems, the p.Glu390Gly variant showed 72.7% residual enzyme activity (Zurflüh et al. 2008), while expression in COS-7 cells revealed that the p.[Glu390Gly];[Arg408Trp] genotype, a recurrent genotype in European and Middle Eastern populations, showed 8.3% residual activity compared to wild type (Danecka et al. 2015). Based on the collective evidence, the p.Glu390Gly 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.
CeGaT Center for Human Genetics Tuebingen	RCV000078503	SCV001247322	pathogenic	not provided	2021-12-01	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000000657	SCV001366426	pathogenic	Phenylketonuria	2019-08-16	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM2,PM3_VS,PP3,PP4_M.
Revvity Omics, Revvity	RCV000000657	SCV002016501	pathogenic	Phenylketonuria	2020-11-20	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000078503	SCV002047254	pathogenic	not provided	2020-10-21	criteria provided, single submitter	clinical testing	The variant has been reported in multiple homozygous and compound heterozygous individuals affected with mild hyperphenylalaninemia or mild PKU and has been characterized as BH4-responsive in the published literature (PMID: 10472529 (1999), 19394257 (2009), 21147011 (2011), 22300847 (2012), 26803807 (2016), 31623983 (2019)). Functional studies have shown this variant reduces PAH activity to 42-62% (PMID: 21147011 (2011), 22300847 (2012), 26803807 (2016)).
Institute of Human Genetics, University of Leipzig Medical Center	RCV000000657	SCV004027717	pathogenic	Phenylketonuria	2023-07-26	criteria provided, single submitter	clinical testing	Criteria applied: PM3_VSTR,PP4_MOD,PM2_SUP,PP3
Baylor Genetics	RCV000000657	SCV004201361	pathogenic	Phenylketonuria	2024-03-30	criteria provided, single submitter	clinical testing
Molecular Genetics, Royal Melbourne Hospital	RCV003993726	SCV004812287	pathogenic	Mild hyperphenylalaninemia	2023-04-11	criteria provided, single submitter	clinical testing	This sequence change in PAH is predicted to replace glutamic acid with glycine at codon 390, p.(Glu390Gly). The glutamic acid residue is highly conserved (100 vertebrates, UCSC), and is located in BH4 AAA hydroxyl domain. There is a moderate physicochemical difference between glutamic acid and glycine. The highest population minor allele frequency in the population database gnomAD v2.1 is 0.016% (21/129,082 alleles) in the European (non-Finnish) population, which is consistent with phenylalanine hydroxylase deficiency. This variant has been detected in multiple individuals with mild hyperphenylalaninaemia (MHP) in the homozygous state and compound heterozygous with a second pathogenic allele. It is one of the most common variants associated with the MHP phenotype (PMID: 31623983, 32668217). Computational evidence predicts a deleterious effect for the missense substitution (REVEL = 0.973). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as PATHOGENIC. Following criteria are met: PM3_VeryStrong, PP3_Moderate, PM2_Supporting.
Institute of Immunology and Genetics Kaiserslautern	RCV000000657	SCV005043024	pathogenic	Phenylketonuria	2024-04-25	criteria provided, single submitter	clinical testing	ACMG Criteria: PM2, PP3, PS3, PM3, PP5; Variant was found in heterozygous state
Mayo Clinic Laboratories, Mayo Clinic	RCV000078503	SCV005414102	pathogenic	not provided	2024-03-19	criteria provided, single submitter	clinical testing	PP3, PM2, PM3_very_strong
OMIM	RCV000000656	SCV000020806	pathogenic	Hyperphenylalaninemia	1999-08-01	no assertion criteria provided	literature only
OMIM	RCV000000657	SCV000020807	pathogenic	Phenylketonuria	1999-08-01	no assertion criteria provided	literature only
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000078503	SCV000119363	not provided	not provided		no assertion provided	not provided
Natera, Inc.	RCV000000657	SCV001463117	pathogenic	Phenylketonuria	2020-09-16	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003914792	SCV004731975	pathogenic	PAH-related disorder	2023-12-07	no assertion criteria provided	clinical testing	The PAH c.1169A>G variant is predicted to result in the amino acid substitution p.Glu390Gly. This variant has been mainly reported to be causative for mild hyperphenylalaninemia (HPA; Guldberg et al. 1994. PubMed ID: 8088845; Bénit et al. 1999. PubMed ID: 10479481; Dobrowolski et al. 2011. PubMed ID: 21147011; Table S3 in Hillert et al. 2020. PubMed ID: 32668217). The p.Glu390Gly substitution has been reported to result in a PAH protein that is responsive to tetrahydrobiopterin (BH4) (Zurflüh et al. 2008. PubMed ID: 17935162). This variant has been classified as pathogenic by the ClinGen PAH Variant Curation Expert Panel, as well as multiple outside laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/625/). This variant is reported in 0.016% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic.