ClinVar Miner

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

dbSNP: rs62516147
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Total submissions: 4
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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

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