Submissions for variant NM_000277.3(PAH):c.442-1G>A

dbSNP: rs62514907

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000000625	SCV000852173	pathogenic	Phenylketonuria	2018-08-05	reviewed by expert panel	curation	PAH-specific ACMG/AMP criteria applied: PM2: Not present in ExAC or 1000 genomes (PMID:9860305); PVS1: Canonical -1 splice site; PP4_Moderate: Reported in a mild PKU patient. BH4 deficiency assessed. (PMID:14681498). In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM2, PVS1, PP4_Moderate).
Eurofins Ntd Llc (ga)	RCV000088924	SCV000230888	pathogenic	not provided	2014-08-08	criteria provided, single submitter	clinical testing
GeneDx	RCV000088924	SCV000577484	pathogenic	not provided	2017-03-28	criteria provided, single submitter	clinical testing	The c.442-1 G>A pathogenic variant in the PAH gene has previously beenreported in association with both mild and classic PKU (Liang et al., 2014; Wang et al., 1991). Thec.442-1 G>A variant destroys the canonical splice acceptor site in intron 4, and is expected to causeabnormal gene splicing. The c.442-1 G>A variant is not observed in large population cohorts (Lek etal., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). It is unclear whether or notc.442-1 G>A is responsive to BH4 therapy (Zurfluh et al., 2008). In summary, we interpret c.442-1G>A as pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000000625	SCV001361328	pathogenic	Phenylketonuria	2019-09-27	criteria provided, single submitter	clinical testing	Variant summary: PAH c.442-1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Five predict the variant abolishes a 3 acceptor site and creates a new cryptic exonic one. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251264 control chromosomes (gnomAD). c.442-1G>A has been reported in the literature in multiple individuals, including compound heterozygotes and homozygotes, affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (e.g. Lee_2004, Liang_2014). These data indicate that the variant is very likely to be associated with disease. Experimental evidence evaluating an impact on protein function determined the variant to confer null PAH activity in vitro (Liang_2014). Two ClinVar submitters including an expert panel (ClinGen PAH Variant Curation Expert Panel) (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000000625	SCV001400309	pathogenic	Phenylketonuria	2023-10-16	criteria provided, single submitter	clinical testing	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). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with hyperphenylalaninemia (PMID: 1998345, 24401910, 29499199). It is commonly reported in individuals of Chinese ancestry (PMID: 1998345, 24401910, 29499199). ClinVar contains an entry for this variant (Variation ID: 594). 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.
Baylor Genetics	RCV000000625	SCV004201339	pathogenic	Phenylketonuria	2024-03-21	criteria provided, single submitter	clinical testing
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV000000625	SCV005418276	pathogenic	Phenylketonuria		criteria provided, single submitter	clinical testing	PVS1+PM2_Supporting+PM3_Strong+PP4_Moderate
OMIM	RCV000000625	SCV000020775	pathogenic	Phenylketonuria	1991-06-01	no assertion criteria provided	literature only
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000088924	SCV000119523	not provided	not provided		no assertion provided	not provided
Natera, Inc.	RCV000000625	SCV001455106	pathogenic	Phenylketonuria	2020-09-16	no assertion criteria provided	clinical testing