Submissions for variant NM_000277.3(PAH):c.611A>G (p.Tyr204Cys)

gnomAD frequency: 0.00001  dbSNP: rs62514927

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000000621	SCV001572875	pathogenic	Phenylketonuria	2021-03-26	reviewed by expert panel	curation	The c.611A>G (p.Tyr204Cys) variant in PAH has been reported in multiple individuals with Classic PKU and MHP (BH4 deficiency excluded). (PMID: 15503242). This variant has a MAF (0.00016) in gnomAD. This variant creates a fully active, novel 5 ́ donor splice site which results in an aberrantly spliced mRNA with a 96-nt deletion at the 3 ́-end of exon 6 PMID: 8990021 (aka Ex6-96A>G). Multiple lines of computational evidence support a deleterious effect. This variant was detected in trans with multiple pathogenic variants including: p.R111* (2); c.442-1G>A; p.R158W; p.L255S; p.P281L; p.K363Nfs*37; p.V399V; p.R408W; p.R241C (2); p.R243Q; p.R261Q (2); p.S349A; p.R413P; p.A434D (2) (PMID: 26322415). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PP4_Moderate, PM3_very-strong, PP3.
GeneDx	RCV000089007	SCV000329866	pathogenic	not provided	2017-07-20	criteria provided, single submitter	clinical testing	The c.611 A>G variant in the PAH is a common pathogenic variant in Chinese patients with phenylketonuria (PKU) and is associated with a classic PKU phenotype (Lee et al., 2004; Yu et al., 2008; Chen et al., 2015). Functional analysis of c.611 A>G found that results in abnormal splicing and it is classified as a not responsive to tetrahydrobiopterin (BH4) therapy (Ellingsen et al., 1997; Sarkissian et al., 2012))
Fulgent Genetics, Fulgent Genetics	RCV000000621	SCV000893948	pathogenic	Phenylketonuria	2018-10-31	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000000621	SCV000917932	pathogenic	Phenylketonuria	2018-12-13	criteria provided, single submitter	clinical testing	Variant summary: PAH c.611A>G (p.Tyr204Cys) results in a non-conservative amino acid change located in the Aromatic amino acid hydroxylase, C-terminal domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Four predict the variant creates a 5' donor site. One publication reports experimental evidence showing that this variant affects mRNA splicing resulting in a 32-amino acid deletion in the core region of the PAH enzyme (Ellingsen_1997). The variant allele was found at a frequency of 1.2e-05 in 246108 control chromosomes (gnomAD). The variant, c.611A>G, has been reported in the literature in multiple individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (Tao_2015, Liang_2014, Song_2005, Ellingsen_1997). These data indicate that the variant is very likely to be associated with disease. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000000621	SCV000950704	pathogenic	Phenylketonuria	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 204 of the PAH protein (p.Tyr204Cys). RNA analysis indicates that this missense change induces altered splicing and likely results in the loss of 32 amino acid residue(s), but is expected to preserve the integrity of the reading-frame. This variant is present in population databases (rs62514927, gnomAD 0.02%). This missense change has been observed in individual(s) with phenylketonuria (PMID: 2589491, 15503242, 18985011). 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: 590). 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%. Studies have shown that this missense change results in the activation of a cryptic splice site in exon 6 (PMID: 8990021). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV000000621	SCV001163722	pathogenic	Phenylketonuria	2024-03-12	criteria provided, single submitter	clinical testing
OMIM	RCV000000621	SCV000020771	pathogenic	Phenylketonuria	1992-05-01	no assertion criteria provided	literature only
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000089007	SCV000119611	not provided	not provided		no assertion provided	not provided
Counsyl	RCV000000621	SCV000220596	pathogenic	Phenylketonuria	2018-10-22	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000000621	SCV001453119	pathogenic	Phenylketonuria	2020-09-16	no assertion criteria provided	clinical testing