Submissions for variant NM_000277.3(PAH):c.975C>G (p.Tyr325Ter)

dbSNP: rs62508573

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000410321	SCV001370855	pathogenic	Phenylketonuria	2020-04-13	reviewed by expert panel	curation	The c.975C>G (p.Tyr325Ter) is a variant in PAH is a null variant (nonsense variant) in a gene where LOF is a known mechanism of disease, leading to premature truncation and NMD (PVS1). It is present at extremely low frequencies in ethnically diverse control databases (gnomAD AF 0.00000399; PAH PM2 cutoff: <0.0002) (PM2). It has been identified in at least 13 PKU probands, at least 5 of whom BH4 deficiency was formally excluded (PP4_Moderate), including in trans with pathogenic or likely pathogenic variants in 9 cases, in trans with VUS in two cases, and homozygous in two cases (PM3_VeryStrong). It was first identified in a Korean patient with classic PKU (as confirmed by blood Phe levels) in trans with the N207D variant (pathogenic per PAH VCEP) (PMID: 9452061; PMID: 15503242); BH4 deficiency was excluded by urinary pterin analysis and DPHR assay. It was also found in another four patients with PKU, BH4 deficiency was excluded by urinary pterin analysis and DPHR assay (PMID: 15503242): one in trans with the known pathogenic (per PAH VCEP and in Clinvar) p.R413P variant (patient's PKU phenotype not specified); one with classic PKU in trans with the known pathogenic (per PAH VCEP) p.V388M variant; one with mild hyperphenylalanemia in trans with the ClinVar pathogenic p.Y204C variant; and one in trans with the known pathogenic (per PAH VCEP) p. R243Q variant (PKU phenotype not specified). It has also been found in a Hispanic patient with classic PKU and BH4 deficiency excluded in trans with the pathogenic (per PAH VCEP) p.R261X variant (PMID: 23430918). It has also been found in 9 Chinese PKU cases (PMID: 26503515; PMID: 30050108), BH4 deficiency does not appear to have been ruled out: 2 homozygotes (classic PKU); one classic PKU case in trans with p.EX6-96A>G variant (pathogenic per PAH VCEP); one classic PKU case in trans with c.843-14_-11delCTTT (no PAH VCEP classification); one mild PKU case in trans with p.A434D (pathogenic per PAH VCEP); one mild hyperphenylalanemia case in trans with p.R241C (ClinVar pathogenic, PAH VCEP pathogenic); one classic PKU case in trans with p.Y206C (Likely pathogenic per PAH VCEP); and one mild hyperphenylalanemia case in trans with p.T418P (VUS per PAH VCEP). It is also listed Pathogenic in ClinVar by two labs (variant ID 102921). Classification: Pathogenic Supporting Criteria: PVS1, PM2; PM3_VeryStrong; PP4_Moderate
Counsyl	RCV000410321	SCV000486345	pathogenic	Phenylketonuria	2016-05-13	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000410321	SCV001224687	pathogenic	Phenylketonuria	2023-07-25	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 102921). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. This sequence change creates a premature translational stop signal (p.Tyr325*) 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 (rs62508573, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with phenylketonuria (PMID: 9452061, 26503515).
Baylor Genetics	RCV000410321	SCV005053833	pathogenic	Phenylketonuria	2024-01-30	criteria provided, single submitter	clinical testing
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000089187	SCV000119803	not provided	not provided		no assertion provided	not provided