Submissions for variant NM_000277.3(PAH):c.889C>T (p.Arg297Cys)

gnomAD frequency: 0.00001  dbSNP: rs62642945

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000993622	SCV001146749	likely pathogenic	Phenylketonuria	2019-07-14	reviewed by expert panel	curation	The c.889C>T (p.R297C) variant in PAH has been reported in multiple individuals with PAH deficiency (BH4 deficiency excluded: PMID: 8807331, 21307867). It was detected in trans with the pathogenic variant IVS12nt1 (VarID576; PMID 8807331). This variant has an extremely low allele frequency in gnomAD (7/245782). Two other missense variants at the same codon are pathogenic. (92750). Computational prediction tools and conservation analysis suggest that the c.889C>T variant may impact the protein. Overall, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP3, PM2, PM3, PM5, PP4_moderate.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000993622	SCV001577735	pathogenic	Phenylketonuria	2024-02-24	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 297 of the PAH protein (p.Arg297Cys). This variant is present in population databases (rs62642945, gnomAD 0.02%). This missense change has been observed in individual(s) with hyperphenylalaninemia (PMID: 8807331, 10234516, 21307867, 23357515, 27121329). 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: 102885). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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.Arg297 amino acid residue in PAH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9298832, 25596310, 27121329). 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.
3billion, Medical Genetics	RCV000993622	SCV002572918	pathogenic	Phenylketonuria	2022-09-01	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.002%). Missense changes are a common disease-causing mechanism. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 24401910). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.82; 3Cnet: 0.96). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000102885). Different missense changes at the same codon (p.Arg297His, p.Arg297Leu) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000092750 , VCV000805823). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Fulgent Genetics, Fulgent Genetics	RCV000993622	SCV002807615	pathogenic	Phenylketonuria	2022-05-25	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000993622	SCV004209662	pathogenic	Phenylketonuria	2023-05-29	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000993622	SCV004848749	likely pathogenic	Phenylketonuria	2022-08-26	criteria provided, single submitter	clinical testing	The p.Arg297Cys variant in PAH has been reported in multiple (>10) individuals with phenylalanine hydroxylase deficiency and mild hyperphenylalaninemia, most frequently as compound heterozygotes in trans with other known pathogenic variants (Eiken 1996 PMID: 8807331, Okano 2011 PMID: 21307867, Hillert 2020 PMID: 32668217, Odagiri 2021 PMID: 33803550, Ferreira 2021 PMID: 33465300). This variant has been previously reported in gnomAD in the European (non-Finnish) population (1/68040), and has been reported in ClinVar as likely pathogenic by the ClinGen PAH Variant Curation Expert Panel (Variation ID 102885). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. Two additional variants involving this codon (p.Arg297Leu and p.Arg297His) have been identified in individuals with phenylalanine hydroxylase deficiency and are classified as likely pathogenic or pathogenic by the ClinGen PAH Variant Curation Expert Panel. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive PAH deficiency. ACMG/AMP criteria applied: PM3_Strong, PM5_Strong, PM2_Supporting, PP3.
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000089146	SCV000119757	not provided	not provided		no assertion provided	not provided
Natera, Inc.	RCV000993622	SCV002088639	likely pathogenic	Phenylketonuria	2020-05-01	no assertion criteria provided	clinical testing