Submissions for variant NM_000277.3(PAH):c.168+5G>C

gnomAD frequency: 0.00003  dbSNP: rs62507288

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000088848	SCV000330988	pathogenic	not provided	2015-12-22	criteria provided, single submitter	clinical testing
GeneDx	RCV000088848	SCV000577366	pathogenic	not provided	2020-05-08	criteria provided, single submitter	clinical testing	Non-canonical splice site variant predicted to destroy the natural splice donor site of intron 2; the adjacent exon is in-frame; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 26589311, 26481238, 8364593, 29499199, 21890392, 20082265, 26666653, 25525159, 22330942, 24048906, 20920871, 26413448, 27469133, 25894915, 17096675, 24516753, 28676969, 23430918, 17935162, 23842451, 22513348, 22526846, 26600521, 23856132, 30747360, 31589614, 33101986)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000350592	SCV000919912	pathogenic	Phenylketonuria	2018-04-06	criteria provided, single submitter	clinical testing	Variant summary: PAH c.168+5G>C alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Three predict the variant weakens a 5' donor site. One predicts the variant abolishes a 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4.1e-05 in 121372 control chromosomes. This frequency is not higher than expected for a pathogenic variant in PAH causing Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (4.1e-05 vs 0.0079), allowing no conclusion about variant significance. c.168+5G>C has been reported in the literature in multiple individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria), including numerous homozygous patients. These data indicate that the variant is very likely to be associated with disease. In addition, two overlapping variants (c.168+5G>T and c.168+5G>A) have been reported in patients, suggesting any change to this nucleotide may result in disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and both classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae	RCV000350592	SCV000951830	pathogenic	Phenylketonuria	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change falls in intron 2 of the PAH gene. It does not directly change the encoded amino acid sequence of the PAH protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs62507288, gnomAD 0.007%). This variant has been observed in individuals with hyperphenylalaninemia or phenylketonuria (PMID: 8364593, 21890392, 22330942, 22526846). ClinVar contains an entry for this variant (Variation ID: 102606). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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.
Mendelics	RCV000350592	SCV001138804	pathogenic	Phenylketonuria	2019-05-28	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000088848	SCV001250399	pathogenic	not provided	2019-11-01	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000350592	SCV004201375	pathogenic	Phenylketonuria	2023-10-10	criteria provided, single submitter	clinical testing
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000088848	SCV000119443	not provided	not provided		no assertion provided	not provided
Counsyl	RCV000350592	SCV000789326	pathogenic	Phenylketonuria	2017-02-01	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000350592	SCV002088675	pathogenic	Phenylketonuria	2020-07-17	no assertion criteria provided	clinical testing