Submissions for variant NM_000277.3(PAH):c.505C>T (p.Arg169Cys)

gnomAD frequency: 0.00001  dbSNP: rs281865440

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000111461	SCV001146735	likely pathogenic	Phenylketonuria	2019-08-11	reviewed by expert panel	curation	The c.505C>T (p.Arg169Cys) PAH variant has been identified in at least 3 compound heterozygous probands with mild HPA to classic PKU, with at least 1 proband excluding BH4 deficiency (PMIDs: 28771436, 30050108, 30747360). It has been detected in trans with pathogenic variants Arg243Gln (ClinVar 591), Arg408Gln (ClinVar 577), and c.208_210del (ClinVar 102632). This variant occurs and a very low frequency of 0.00001194 in gnomAD. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_Strong, PM2, PP4_Moderate.
Genome-Nilou Lab	RCV000111461	SCV001810546	likely pathogenic	Phenylketonuria	2021-07-22	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000111461	SCV002060148	likely pathogenic	Phenylketonuria	2021-11-08	criteria provided, single submitter	clinical testing	NM_000277.1(PAH):c.505C>T(R169C) is a missense variant classified as likely pathogenic in the context of phenylalanine hydroxylase deficiency. Please note that the R169C mutation can be associated with any form of this disease. R169C has been observed in cases with relevant disease (PMID: 32668217, 30050108, 28982351, 28771436). Functional assessments of this variant are not available in the literature. R169C has been observed in population frequency databases (gnomAD: SAS 0.003%). In summary, NM_000277.1(PAH):c.505C>T(R169C) is a missense variant that has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000111461	SCV002228976	pathogenic	Phenylketonuria	2024-09-27	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 169 of the PAH protein (p.Arg169Cys). This variant is present in population databases (rs281865440, gnomAD 0.003%). This missense change has been observed in individual(s) with PAH-related conditions (PMID: 28771436, 32668217; BIOPKU http://www.biopku.org). ClinVar contains an entry for this variant (Variation ID: 125436). 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) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PAH protein function. This variant disrupts the p.Arg169 amino acid residue in PAH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10234516, 18299955, 21147011, 26666653, 28982351, 30459323). 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.
Baylor Genetics	RCV000111461	SCV004201358	likely pathogenic	Phenylketonuria	2024-03-18	criteria provided, single submitter	clinical testing
GeneDx	RCV004719694	SCV005325368	pathogenic	not provided	2024-02-27	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26503515, 29499199, 32668217, 30050108, 28771436, 29316886, 21147011, 36845377)
Inserm U 954, Faculté de Médecine de Nancy	RCV000111461	SCV000143858	probable-pathogenic	Phenylketonuria		no assertion criteria provided	not provided	Converted during submission to Likely pathogenic.