Submissions for variant NM_000277.3(PAH):c.509+1G>A

dbSNP: rs63102461

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV001057888	SCV001370860	pathogenic	Phenylketonuria	2020-05-14	reviewed by expert panel	curation	Variant c.509+1G>A in PAH was found in 1 Chinese patient with Phe levels >120 umol/L (PMID: 26322415). BH4 deficiency was excluded by analysis of urinary pterins and dihydropteridine reductase activity in erythrocytes (PP4-Moderate). This null variant, canonical +1 splice site, is in a gene where LOF is a known mechanism of disease. Exon skipping disrupts reading frame. Predicted to undergo NMD, not located in last exon or last 50bp of preliminary exon. Coding exon number 5 out of 13 coding exons (PVS1). Variant identified in 1/66684 European alleles in ExAC. This variant is present in European (non-Finnish) populations at a frequency of 0.00001 (Gnomad, ExAC) (PM2). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PP4-Moderate.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001057888	SCV001222409	pathogenic	Phenylketonuria	2023-07-28	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. ClinVar contains an entry for this variant (Variation ID: 102707). Disruption of this splice site has been observed in individual(s) with hyperphenylalaninemia and phenylketonuria (PMID: 8889590, 26666653, 29499199). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs63102461, gnomAD 0.0009%). This sequence change affects a donor splice site in intron 5 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).
Revvity Omics, Revvity	RCV001057888	SCV002016481	pathogenic	Phenylketonuria	2020-03-27	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001057888	SCV002766007	pathogenic	Phenylketonuria	2022-11-25	criteria provided, single submitter	clinical testing	Variant summary: PAH c.509+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: four predict the variant abolishes a 5' splicing donor site. The variant allele was found at a frequency of 4e-06 in 251342 control chromosomes. c.509+1G>A has been reported in the literature in multiple individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (e.g. Guldberg_1996, Zhu_2010, Quirk_2012, Reblova_2013, Jeannesson-Thivisol_2015). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Fout ClinVar submitters including an expert panel (evaluation after 2014) have classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV001057888	SCV004209595	pathogenic	Phenylketonuria	2023-09-07	criteria provided, single submitter	clinical testing
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV001057888	SCV005417675	pathogenic	Phenylketonuria		criteria provided, single submitter	clinical testing	PVS1+PM2_Supporting+PP4_Moderate
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000088955	SCV000119558	not provided	not provided		no assertion provided	not provided
Natera, Inc.	RCV001057888	SCV002088663	pathogenic	Phenylketonuria	2020-07-07	no assertion criteria provided	clinical testing