Submissions for variant NM_000277.3(PAH):c.1259G>T (p.Arg420Met)

gnomAD frequency: 0.00001  dbSNP: rs767075719

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV001200002	SCV001370854	likely pathogenic	Phenylketonuria	2020-05-21	reviewed by expert panel	curation	The c.1259G>T (p.Arg420Met) variant in PAH has been reported in 1 Spanish patient with mild hyperphenylalaninemia (BH4 deficiency excluded) (PP4_Moderate; PMID: 27121329). This variant was detected with p.A403V (Pathogenic in ClinVar, VarID:92731, 18 submitters) (PM3; PMID: 27121329). This variant has a MAF of 0.00002 in population databases (PM2). This variant is predicted deleterious by SIFT, PolyPhen2, MutationTaster, and REVEL = 0.835 (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PP4_Moderate, PP3, PM3.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001200002	SCV002300548	likely pathogenic	Phenylketonuria	2024-11-05	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with methionine, which is neutral and non-polar, at codon 420 of the PAH protein (p.Arg420Met). This variant is present in population databases (rs767075719, gnomAD 0.002%). This missense change has been observed in individual(s) with hyperphenylalaninemia (PMID: 23500595, 35281663; internal data). 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: 932268). 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.Ile421 amino acid residue in PAH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22526846). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV001200002	SCV002795475	likely pathogenic	Phenylketonuria	2022-02-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001200002	SCV003800708	likely pathogenic	Phenylketonuria	2023-01-30	criteria provided, single submitter	clinical testing	Variant summary: PAH c.1259G>T (p.Arg420Met) results in a non-conservative amino acid change located in the Aromatic amino acid hydroxylase, C-terminal (IPR019774) of the encoded protein sequence. Five 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 251446 control chromosomes. c.1259G>T has been reported in the literature as a heterozygous genotype with a pathogenic variant in individuals (Aldamiz_2016, Martin-Rivada_2022) and in one individual without a specified genotype (Yubero_2016, etc) affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters, including an expert panel, classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Baylor Genetics	RCV001200002	SCV004209627	likely pathogenic	Phenylketonuria	2024-02-19	criteria provided, single submitter	clinical testing
GeneDx	RCV004720084	SCV005326088	likely pathogenic	not provided	2023-10-27	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27243974, 23500595, 27121329, 35281663, 32668217, 30674554)