Submissions for variant NM_000277.3(PAH):c.1063C>T (p.Gln355Ter)

dbSNP: rs199475633

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV001234044	SCV004222634	pathogenic	Phenylketonuria	2023-10-15	reviewed by expert panel	curation	The c.1063C>T (p.Gln355Ter) variant in PAH has been reported in a German PKU patient. (PP4; PMID: 10394930). This variant is absent from population databases (PM2_supporting). It is a null variant (nonsense) in exon 10/13 (NMD predicted) in PAH, a gene where loss of function is a known mechanism of disease (PVS1). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2_supporting, PP4.
Invitae	RCV001234044	SCV001406670	pathogenic	Phenylketonuria	2024-01-24	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln355*) 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 premature translational stop signal has been observed in individual(s) with another GENE variant in an individual, several individuals, a family, several families affected with hyperphenylalaninemia (PMID: 28982351). ClinVar contains an entry for this variant (Variation ID: 102500). 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.
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000088731	SCV000119313	not provided	not provided		no assertion provided	not provided