Submissions for variant NM_000277.3(PAH):c.1200-1G>A

gnomAD frequency: 0.00001  dbSNP: rs62507322

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV001201306	SCV001448299	pathogenic	Phenylketonuria	2020-10-15	reviewed by expert panel	curation	This c.1200-1G>A variant in PAH was reported in 2 Caucasian patients with PAH deficiency (PMID: 23430918) detected with pathogenic variants p.Phe55Leu and c.1315+1G>A. A defect in BH4 metabolism was not excluded. This variant is absent from population databases. This variant in the -1 splice acceptor site results in exon skipping, which disrupts the reading frame and is predicted to undergo nonsense mediated decay. The exon is present in biologically-relevant transcripts. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PM3, PP4.
Eurofins Ntd Llc (ga)	RCV000078505	SCV000110361	pathogenic	not provided	2015-07-27	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001201306	SCV001372445	likely pathogenic	Phenylketonuria	2020-06-21	criteria provided, single submitter	clinical testing	Variant summary: PAH c.1200-1G>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: Two predict the variant abolishes a 3' acceptor site. Two predict the variant weakens a 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251412 control chromosomes. c.1200-1G>A has been reported in the PKU database and in literature in individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) and has been subsequently cited by others (example, Nowacki_1998, Rajabi_2019, Liu_2017). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Invitae	RCV001201306	SCV001380354	pathogenic	Phenylketonuria	2024-01-16	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 11 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 phenylketonuria (PMID: 28982351, 31623983). ClinVar contains an entry for this variant (Variation ID: 92730). 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	RCV001201306	SCV004209647	pathogenic	Phenylketonuria	2023-07-06	criteria provided, single submitter	clinical testing
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000078505	SCV000119385	not provided	not provided		no assertion provided	not provided