Submissions for variant NM_000277.3(PAH):c.809G>A (p.Arg270Lys)

gnomAD frequency: 0.00002  dbSNP: rs62514950

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000153632	SCV001370805	pathogenic	Phenylketonuria	2020-06-08	reviewed by expert panel	curation	The c.809G>A (p.Arg270Lys) variant in PAH has been reported in multiple individuals with PAH deficiency (BH4 deficiency excluded). (PMID: 21871829, 23856132). This variant has an extremely low allele frequency (MAF=0.00016) in gnomAD. This variant has 11% residual PAH activity (PMID: 27620137). This variant was detected with multiple pathogenic variants: IVS10nt-11G>A (2 patients), L348V, S349P, R158Q, E390G, D415N (PMID: 21871829); and IVS4+5G>T (PMID: 23856132). Computational prediction tools and conservation analysis support a deleterious effect. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_very-strong, PM2, PP4_Moderate, PP3, PS3_supporting.
Eurofins Ntd Llc (ga)	RCV000089105	SCV000203180	pathogenic	not provided	2014-01-15	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000153632	SCV000629217	pathogenic	Phenylketonuria	2024-11-05	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with lysine, which is basic and polar, at codon 270 of the PAH protein (p.Arg270Lys). This variant is present in population databases (rs62514950, gnomAD 0.009%). This missense change has been observed in individual(s) with phenylketonuria and hyperphenylalaninemia (PMID: 12173030, 20082265, 20187763, 23500595, 23856132). ClinVar contains an entry for this variant (Variation ID: 102846). 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 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: 16545551, 17935162, 25453233, 27620137). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000153632	SCV000696467	pathogenic	Phenylketonuria	2017-07-05	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000089105	SCV001249179	pathogenic	not provided	2019-02-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000089105	SCV002568584	pathogenic	not provided	2022-05-18	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 8528673, 11180595, 20082265, 20187763, 23856132, 29749107, 34828281, 17935162, 25750018, 27620137, 9598724, 7914195, 12173030, 16545551, 25453233, 23500595, 21871829, 26666653, 31355225, 32778825, 33465300)
Baylor Genetics	RCV000153632	SCV004209703	pathogenic	Phenylketonuria	2024-01-26	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000089105	SCV004222249	pathogenic	not provided	2022-01-25	criteria provided, single submitter	clinical testing	The variant has been reported in multiple individuals largely affected with classic PKU when another severe disease-causing variant is present on the other allele (PMID: 20082265 (2010), 21871829 (2011), 23856132 (2013), 26666653 (2015), 33465300 (2021)). Functional studies have shown that this variant causes severely reduced activity ranging from 2.1 to 11% of the wild-type activity (PMID: 16545551 (2006), 27620137 (2016)). Based on the available information, this variant is classified as pathogenic.
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000089105	SCV000119712	not provided	not provided		no assertion provided	not provided
Natera, Inc.	RCV000153632	SCV002088644	pathogenic	Phenylketonuria	2020-11-06	no assertion criteria provided	clinical testing