Submissions for variant NM_000277.3(PAH):c.977G>A (p.Trp326Ter)

dbSNP: rs62514959

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000000609	SCV001370856	pathogenic	Phenylketonuria	2020-04-13	reviewed by expert panel	curation	The c.977G>A (p.Trp326Ter) 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 five PKU cases in whom BH4 deficiency was excluded (PP4_Moderate), in four cases in trans with known pathogenic variants (PM3_VeryStrong). It has been identified in at least two Chinese classic PKU cases (PMID: 261600; PMID: 1301927; PMID: 28982351), in trans with the known pathogenic (per PAH VCEP) p.Y356X and p.R243Q variants; as a single heterozygous variant in a Chinese classic PKU case with BH4 deficiency excluded (PMID: 24705691); in trans with the known pathogenic (per PAH VCEP) p.R261Q variant in one Slovak case with classic PKU with BH4 deficiency said to be excluded (PMID: 23764561); one Chinese proband with mild hyperphenylalanemia in trans with c.1197A>T (p.V399V) (PMID: 25456745). It is also listed Pathogenic in ClinVar by three labs (variant ID 579). Classification: Pathogenic Supporting Criteria: PVS1, PM2; PM3_VeryStrong; PP4_Moderate
Counsyl	RCV000000609	SCV000799431	pathogenic	Phenylketonuria	2018-04-20	criteria provided, single submitter	clinical testing
Invitae	RCV000000609	SCV001586285	pathogenic	Phenylketonuria	2021-03-29	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant has been observed in individual(s) with hyperphenylalaninemia (PMID: 29499199). ClinVar contains an entry for this variant (Variation ID: 579). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Trp326*) 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).
Baylor Genetics	RCV000000609	SCV004209654	pathogenic	Phenylketonuria	2023-06-17	criteria provided, single submitter	clinical testing
OMIM	RCV000000609	SCV000020759	pathogenic	Phenylketonuria	1989-11-01	no assertion criteria provided	literature only
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000089188	SCV000119804	not provided	not provided		no assertion provided	not provided