Submissions for variant NM_000277.3(PAH):c.601C>T (p.His201Tyr)

dbSNP: rs62517205

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000509208	SCV001250523	likely pathogenic	Phenylketonuria	2019-11-10	reviewed by expert panel	curation	The c.601C>T (p.His201Tyr) variant in PAH has been reported in multiple individuals with PAH deficiency (BH4 deficiency excluded). (PP4_Moderate; PMID: 16198137). This variant is at a ow frequency in controls (3.964e-6 in gnomAD; PM2). This variant was detected with known pathogenic variants IVS10nt546 (PMID: 9521426) and R158Q (PMID: 16198137; PM3_strong). Computational evidence is conflicting. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3_strong.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000509208	SCV000629203	pathogenic	Phenylketonuria	2024-02-02	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 201 of the PAH protein (p.His201Tyr). This variant is present in population databases (rs62517205, gnomAD 0.0009%). This missense change has been observed in individual(s) with hyperphenylalaninemia (PMID: 9521426, 10598814, 16198137, 23792259). 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: 102752). 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%. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000588479	SCV000696446	pathogenic	Hyperphenylalaninemia	2017-04-13	criteria provided, single submitter	clinical testing	Variant summary: The PAH c.601C>T (p.His201Tyr) variant located in the Aromatic amino acid hydroxylase, C-terminal (via InterPro) involves the alteration of a conserved nucleotide and 3/5 in silico tools predict a damaging outcome. Reblova_2013 indicates that the His201 plays a key role in forming a H-bond needed for stablization. This variant is absent in 121300 control chromosomes (ExAC). Multiple publications have cited the variant in affected compound heterozygote individuals, predominantly from Italy, with a mild HPA. Taken together, the variant of interest has been classified as "pathogenic."
GeneDx	RCV000089001	SCV002513156	pathogenic	not provided	2022-05-03	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: 23357515, 23792259, 10598814, 35023679, 32668217, 9521426, 16198137)
Baylor Genetics	RCV000509208	SCV004209571	likely pathogenic	Phenylketonuria	2024-03-18	criteria provided, single submitter	clinical testing
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000089001	SCV000119605	not provided	not provided		no assertion provided	not provided
Counsyl	RCV000509208	SCV001132448	likely pathogenic	Phenylketonuria	2017-03-15	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000509208	SCV001453120	pathogenic	Phenylketonuria	2020-09-16	no assertion criteria provided	clinical testing