Submissions for variant NM_000277.3(PAH):c.1065+1G>A

dbSNP: rs62516147

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000411856	SCV001572874	likely pathogenic	Phenylketonuria	2021-03-21	reviewed by expert panel	curation	The PAH variant c.1065+1G>A (IVS10+1G>A) affects the canonical splice site (donor site). Loss of function in the PAH gene is a known mechanism of disease. Exon skipping is predicted to not disrupt the reading frame. This variant is predicted to alter a region that is critical to protein function. The PAH variant c.1065+1G>A (IVS10+1G>A) was identified in two French patients with mild hyperphenylalaninemia (mHP, 180 < Phe < 600 μmol/L) with the likely pathogenic variant c.261C>A (p.Ser87Arg) and with the pathogenic variant c.1169A>G (p.Glu390Gly)(PMID: 26666653). The PAH variant c.1065+1G>A was also reported in an European patient with PAH deficiency (PMID: 10679941). According to gnomAD, the PAH variant c.1065+1G>A (IVS10+1G>A) is present at a low allele frequency in population databases, with the highest reported frequency in the European (Finnish) population (0.00005). 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.
Counsyl	RCV000411856	SCV000486870	pathogenic	Phenylketonuria	2016-08-26	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000411856	SCV002240083	pathogenic	Phenylketonuria	2022-03-17	criteria provided, single submitter	clinical testing	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. ClinVar contains an entry for this variant (Variation ID: 102501). This variant is also known as IVS10+1G>A. Disruption of this splice site has been observed in individual(s) with hyperphenylalaninemia (PMID: 29176022). This variant is present in population databases (rs62516147, gnomAD no frequency). This sequence change affects a donor splice site in intron 10 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).
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000088732	SCV000119314	not provided	not provided		no assertion provided	not provided