Submissions for variant NM_000277.3(PAH):c.612T>G (p.Tyr204Ter)

dbSNP: rs62514928

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000686246	SCV001370844	pathogenic	Phenylketonuria	2020-05-08	reviewed by expert panel	curation	The c.612T>G (p.Tyr204Ter) variant in PAH is a null variant (nonsense variant) in exon 6 of 13 in a gene where LOF is a known mechanism of disease, leading to premature truncation and NMD (PVS1). It is present at extremely low frequency in ethnically diverse control databases, with gnomAD AF 0.00000398 (<0.002, the PAH-specific cutoff) (PM2). It has been reported as a heterozygous variant in at least four PKU cases, with known pathogenic variants in at least two cases (PM3_Strong): with a Sicilian PKU case with BH4 deficiency excluded (PMID: 8268925) (PP4_Moderate); in a German PKU case (PMID: 10394930); in one Spanish case with the pathogenic (per PAH VCEP) p.R176L variant (PMID: 10234516); and in one family (2 affected siblings) and 2 additional mild PKU patients with the pathogenic (per PAH VCEP) p.R68S variant (PMID: 23514811). It has also been reported Pathogenic by three labs in ClinVar (variation ID 102758). Classification: Pathogenic Supporting criteria: PVS1, PM2; PM3_Strong; PP4_Moderate
GeneDx	RCV000089008	SCV000490680	pathogenic	not provided	2016-03-29	criteria provided, single submitter	clinical testing	The Y204X variant in the PAH gene has been reported as a pathogenic variant in the PAH Consortium database. The Y204X nonsense variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Patients who are homozygous for Y204X are reported to have classic PKU and are not responsive to BH4 therapy (Guldberg et al., 1993; BIOPKU database). Therefore, we interpret Y204X to be a pathogenic variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000686246	SCV000813756	pathogenic	Phenylketonuria	2025-01-23	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Tyr204*) in the PAH gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PAH are known to be pathogenic (PMID: 1301187, 9634518). This variant is present in population databases (rs62514928, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with phenylketonuria and hyperphenylalaninemia (PMID: 8268925, 23764561, 27121329, 27264808). ClinVar contains an entry for this variant (Variation ID: 102758). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000686246	SCV001361331	pathogenic	Phenylketonuria	2019-11-22	criteria provided, single submitter	clinical testing	Variant summary: PAH c.612T>G (p.Tyr204X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4e-06 in 251338 control chromosomes (gnomAD). c.612T>G has been reported in the literature in multiple individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria)(Aldamiz-Echevarria_2016, Sarkissian_2011). These data indicate that the variant is very likely to be associated with disease. Two ClinVar submissions (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000686246	SCV002811617	pathogenic	Phenylketonuria	2021-11-22	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000686246	SCV004201347	pathogenic	Phenylketonuria	2024-03-07	criteria provided, single submitter	clinical testing
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000089008	SCV000119612	not provided	not provided		no assertion provided	not provided