ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.970-1G>A

gnomAD frequency: 0.00001  dbSNP: rs202183605
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen PAH Variant Curation Expert Panel RCV000106379 SCV001370829 likely pathogenic Phenylketonuria 2020-04-30 reviewed by expert panel curation The c.970-1G>A variant in PAH is a splice-site variant predicted to result in skipping of exon 10, which is a key region of the encoded enzyme (PVS1_Strong). It is absent from ethnically diverse control databases, including gnomAD/ExAC, 1000 Genomes, and ESP (PM2). It is reported Likely Pathogenic for PKU in Clinvar by a single lab (ID 120298), without further information. It has also been reported in the BioPKU database as an online submission in 2013, without further information. Classification: Likely Pathogenic Supporting ACMG criteria: PVS1_Strong, PM2
Invitae RCV000106379 SCV004373529 pathogenic Phenylketonuria 2023-06-15 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: 120298). Disruption of this splice site has been observed in individual(s) with hyperphenylalaninemia (PMID: 28676969, 32668217; BIOPKU http://www.biopku.org). This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 9 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).
Inserm U 954, Faculté de Médecine de Nancy RCV000106379 SCV000143879 probable-pathogenic Phenylketonuria no assertion criteria provided not provided Converted during submission to Likely pathogenic.

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