Submissions for variant NM_000277.3(PAH):c.969+1G>A

dbSNP: rs62508584

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000797251	SCV001572853	likely pathogenic	Phenylketonuria	2020-04-21	reviewed by expert panel	curation	The PAH variant c.969+1G>A (IVS9+1G>A) is a null variant (donor site) located in exon number 9 of the PAH gene. Loss of function in the PAH gene is a known mechanism of disease. Four null variants in exon 9 of the PAH gene have been reported. This variant is predicted to alter a region that is critical to protein function (13 pathogenic non-nonsense variants in the skipped exon have been reported). Exon skipping is not predicted to disrupt the reading frame. According to TraP in silico splicing prediction, this alteration is probably damaging (TraP score 0.968). HSF (-32.06% variation) and MaxEnt (-86.2% variation) agree that this alteration of the WT donor site most probably affects splicing. The PAH variant c.969+1G>A (IVS9+1G>A) was reported with the PAH pathogenic variant c.1222C>T (p.Arg408Trp) (ClinVar ID: 577) in a European patient with classical PKU (serum Phe levels above 1200μmol/L). Cofactor deficiency was excluded by the BH4 test (PMID: 10679941) and in a patient from Iran with classical PKU (serum Phe levels above 1200μmol/L) (PMID: 26413448). This variant is absent in the gnomAD, ExAC, and PAGE population databases. In summary, this variant meets the criteria to be classified as likely pathogenic. PAH-specific ACMG/AMP criteria applied: PM2, PM3_Supporting, PP4, and PVS1_Strong.
Invitae	RCV000797251	SCV000936800	pathogenic	Phenylketonuria	2021-08-24	criteria provided, single submitter	clinical testing
3billion	RCV000797251	SCV002058454	pathogenic	Phenylketonuria	2022-01-03	criteria provided, single submitter	clinical testing	Canonical splice site: predicted to alter splicing and result in a loss or disruption of normal protein function through protein truncation. Multiple pathogenic variants are reported in the predicted truncated region (PVS1_VS). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). The variant has been reported multiple times as an established pathogenic/likely pathogenic variant (ClinVar ID: VCV000102914). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000089179	SCV000119794	not provided	not provided		no assertion provided	not provided