Submissions for variant NM_000277.3(PAH):c.1200-8G>A

dbSNP: rs62507261

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000525956	SCV001146703	likely pathogenic	Phenylketonuria	2019-09-29	reviewed by expert panel	curation	The c.1200-8G>A variant in PAH has been reported in multiple patients with PAH deficiency. BH4 deficiency excluded (PMID: 9391881, 23062575). This variant has extremely low frequency in gnomAD (MAF=0.00001) (PM2). This variant was detected with known pathogenic variants IVS10-11G>A, p.A403V (PM3). Computational evidence supports a splicing effect (HSF and MaxEnt). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3, PP3.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000525956	SCV000629179	pathogenic	Phenylketonuria	2021-06-10	criteria provided, single submitter	clinical testing	This sequence change falls in intron 11 of the PAH gene. It does not directly change the encoded amino acid sequence of the PAH protein. 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 combination with another PAH variant in several individuals affected with classical phenylketonuria (PMID: 9391881, 30459323). This variant is not present in population databases (ExAC no frequency).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000525956	SCV004222801	pathogenic	Phenylketonuria	2023-11-17	criteria provided, single submitter	clinical testing	Variant summary: PAH c.1200-8G>A 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: two predict the variant abolishes a 3' acceptor site, two predict the variant weakens the same 3' acceptor site, and two predict the variant creates a 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-06 in 251396 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1200-8G>A has been reported in the literature in multiple individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (e.g., Kozak_1997, Bardelli_2002, Chen_2018, Hennermann_2012, Hillert_2020). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 12409276, 30459323, 23062575, 32668217, 9391881). Three submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000088799	SCV000119387	not provided	not provided		no assertion provided	not provided
Counsyl	RCV000525956	SCV000794779	likely pathogenic	Phenylketonuria	2019-02-26	no assertion criteria provided	clinical testing