Submissions for variant NM_000277.3(PAH):c.1166del (p.Ala389fs)

dbSNP: rs62506949

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000669467	SCV001448230	pathogenic	Phenylketonuria	2020-10-29	reviewed by expert panel	curation	The c.1166del (p.Ala389fs) variant in PAH has been detected in 1 patient with PKU, Phe = 1045umol/L; BH4 deficiency not excluded (PMID: 25323746; PP4). This variant is absent from population databases (PM2), and is a variant predicted to undergo NMD, not located in last exon or last 50bp of preliminary exon. Coding exon number 11 out of 13 coding exons (11 out of total exons) (PVS1). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PP4.
Counsyl	RCV000669467	SCV000794224	likely pathogenic	Phenylketonuria	2017-09-20	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000669467	SCV004294263	pathogenic	Phenylketonuria	2023-10-04	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ala389Glufs*11) 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 not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PAH-related conditions. ClinVar contains an entry for this variant (Variation ID: 102543). For these reasons, this variant has been classified as Pathogenic.
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000088777	SCV000119362	not provided	not provided		no assertion provided	not provided