Submissions for variant NM_000277.3(PAH):c.442-2A>C

dbSNP: rs281865448

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000106357	SCV001448252	pathogenic	Phenylketonuria	2020-07-24	reviewed by expert panel	curation	The c.442-2A>C variant in PAH is a canonical splice acceptor in which exon skipping disrupts the reading frame and is predicted to undergo nonsense mediated-decay. This variant was documented in 3 patients with classic PKU (PMID 26666653, 18937047, 9048935). It was detected with pathogenic variants c.1042C>G and p.Tyr204Cys (PMID 18937047, 9048935). This variant is absent in population databases. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PM3, and PP4.
Counsyl	RCV000106357	SCV000485442	likely pathogenic	Phenylketonuria	2015-12-11	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000106357	SCV002243747	pathogenic	Phenylketonuria	2021-03-26	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has been observed in individual(s) with phenylketonuria (PMID: 9048935). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 120276). This variant is not present in population databases (ExAC no frequency). This sequence change affects an acceptor splice site in intron 4 of the PAH gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in PAH are known to be pathogenic (PMID: 1301187, 9634518).
Baylor Genetics	RCV000106357	SCV005053837	pathogenic	Phenylketonuria	2024-01-10	criteria provided, single submitter	clinical testing
Inserm U 954, Faculté de Médecine de Nancy	RCV000106357	SCV000143856	probable-pathogenic	Phenylketonuria		no assertion criteria provided	not provided	Converted during submission to Likely pathogenic.