ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.842+2T>A

dbSNP: rs62514955
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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 RCV000000645 SCV001370843 pathogenic Phenylketonuria 2020-04-16 reviewed by expert panel curation The c.842+2T>A variant in PAH is a splice-site variant predicted to result in skipping of exon 8, leading to a frameshift, premature protein truncation, and NMD (PVS1). It is absent from ethnically diverse control databases, including gnomAD/ExAC, 1000 Genomes, and ESP (PM2). It is reported Pathogenic in Clinvar (ID 614). It has been reported among multiple patients with classic PKU, with BH4 deficiency formally excluded (PMID: 17557229; PMID: 21307867) (PP4_Moderate) and has been reported in trans with multiple Pathogenic and Likely Pathogenic mutations, including R111X (P, ClinGen); P281L (P, ClinGen); R413P (P, ClinGen); R243Q (P, ClinGen); R261Q (LP/P, ClinGen); R400T (unknown, ClinGen) (PMID: 17557229) (PM3_Strong). Classification: Pathogenic Supporting Criteria: PVS1, PM2, PM3_Strong, PP4_Moderate
Invitae RCV000000645 SCV001213687 pathogenic Phenylketonuria 2024-01-29 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 7 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). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with phenylketonuria (PMID: 26322415, 27264808). This variant is also known as IVS7+2T>A. ClinVar contains an entry for this variant (Variation ID: 614). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000000645 SCV000020795 pathogenic Phenylketonuria 1989-11-01 no assertion criteria provided literature only
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000089131 SCV000119741 not provided not provided no assertion provided not provided

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