Submissions for variant NM_000277.3(PAH):c.463C>T (p.Arg155Cys)

gnomAD frequency: 0.00002  dbSNP: rs539743701

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000669560	SCV001448615	likely pathogenic	Phenylketonuria	2020-10-15	reviewed by expert panel	curation	This c.463C>T (p.Arg155Cys) variant in PAH was reported in at least one patient with mild HPA detected in trans with pathogenic variant p.Gly289Arg (PMID: 27121329). A defect in the synthesis or regeneration pathways of 6R-BH4 was ruled out by analyzing urinary pterin levels as well as by measuring the dihydropteridine reductase activity. Computational evidence supports a deleterious effect. This variant is observed at an amino acid residue where two other pathogenic missense variants have also been observed. This variant is seen at an extremely low frequency in population databases. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM5, PM3, PM2, PP4_moderate, and PP3.
Counsyl	RCV000669560	SCV000794323	uncertain significance	Phenylketonuria	2017-11-14	criteria provided, single submitter	clinical testing
Invitae	RCV000669560	SCV001574358	pathogenic	Phenylketonuria	2023-08-10	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg155 amino acid residue in PAH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18937047, 23932990, 24401910, 26210745, 28754886). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 expected to disrupt PAH protein function. ClinVar contains an entry for this variant (Variation ID: 554011). This missense change has been observed in individual(s) with phenylketonuria (PMID: 23514811). This variant is present in population databases (rs539743701, gnomAD 0.006%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 155 of the PAH protein (p.Arg155Cys).
Fulgent Genetics, Fulgent Genetics	RCV000669560	SCV002815715	pathogenic	Phenylketonuria	2021-09-06	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000669560	SCV002819565	likely pathogenic	Phenylketonuria	2022-12-15	criteria provided, single submitter	clinical testing	Variant summary: PAH c.463C>T (p.Arg155Cys) results in a non-conservative amino acid change located in the Aromatic amino acid hydroxylase, C-terminal domain (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 2e-05 in 251344 control chromosomes. c.463C>T has been reported in the literature in individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria; Bueno_2013, Aldamiz-Echevarria_2016, Hillert_2020). Two other variants affecting the same amino acid have been reported in association with Phenylketonuria in HGMD (R155H, R155P). Two clinical diagnostic laboratories and one expert panel have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation: two submitters classified the variant as VUS and pathogenic, respectively while the ClinGen PAH Variant Curation Expert Panel classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Baylor Genetics	RCV000669560	SCV004209621	pathogenic	Phenylketonuria	2023-08-10	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000669560	SCV004237396	pathogenic	Phenylketonuria	2023-06-08	criteria provided, single submitter	clinical testing