Submissions for variant NM_000277.3(PAH):c.707-1G>A

dbSNP: rs62507269

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000797518	SCV001370815	pathogenic	Phenylketonuria	2020-05-09	reviewed by expert panel	curation	The PAH variant c.707-1G>A (IVS6-1G>A) is a null variant (acceptor site) located in exon number 7 of the PAH gene. Loss of function in the PAH gene is a known mechanism of disease. Eleven null variants in exon 7 of the PAH gene have been reported. This variant causes exon skipping that results in the removal of more than 10% of the transcript. This variant is predicted to disrupt the reading frame, altering regions critical to protein function (63 pathogenic non-nonsense variants in skipped exons have been reported). The mRNA transcript is predicted to undergo NMD. According to TraP in silico splicing prediction, this alteration is probably damaging (TraP score 0.572). HSF (-31.55% variation) and MaxEnt (-114.25% variation) agree that this alteration of the WT acceptor site most probably affects splicing. The PAH variant c.707-1G>A (IVS6-1G>A) was identified in three alleles from Chinese patients with classical PKU. The patients had a plasma Phe level above 120 micromol/L. DHPR activity, biopterin, and/or pteridine analysis was performed to rule out other causes of hyperphenylalaninemia (PMID: 28754886, 30747360). The PAH variant c.707-1G>A (IVS6-1G>A) was detected in two Chinese patients with classic PKU (cPKU Phe more than 1200 micromol/L). These two patients were identified with the likely pathogenic PAH variant c.1285C>A (p.Gln429Lys) (ClinVar ID: 551555) and with the pathogenic PAH variant c.526C>T (p.Arg176Ter) (ClinVar ID: 102723) Pathogenic PM3 Points: 0.75 (Supporting) (PMID: 28754886) This variant is absent in the gnomAD, ExAC , and PAGE population databases. In summary, this variant meets the criteria to be classified as pathogenic. PAH-specific ACMG/AMP criteria applied: PM2, PM3_Supporting, PP4_Moderate, PVS1.
Invitae	RCV000797518	SCV000937078	pathogenic	Phenylketonuria	2018-12-10	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Donor and acceptor splice site variants 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). 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 phenylketonuria (PMID: 28754886, 26322415). This variant is also known as IVS6-1G>A in the literature. ClinVar contains an entry for this variant (Variation ID: 102793). This variant is not present in population databases (ExAC no frequency). This sequence change affects an acceptor splice site in intron 6 of the PAH gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product.
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000089044	SCV000119649	not provided	not provided		no assertion provided	not provided