ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.1315+2T>C (rs1799970)

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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 RCV000169029 SCV000886570 likely pathogenic Phenylketonuria 2018-12-09 reviewed by expert panel curation The c.1315+2T>C variant is at the 3' canonical splice site in the penultimate exon of PAH. It is absent form population databases and has been identified in trans with pathogenic variants in three independent patients (F39del, Y414C, and R261X; PMID: 9452062; 9521426). A defect of BH4 metabolism was excluded as a cause of elevated phenylalanine in all patients. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3_strong.
Counsyl RCV000169029 SCV000220178 likely pathogenic Phenylketonuria 2014-03-18 criteria provided, single submitter literature only
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000169029 SCV001363424 pathogenic Phenylketonuria 2019-01-25 criteria provided, single submitter clinical testing Variant summary: PAH c.1315+2T>C is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5' splicing donor site. One predict the variant creates/strengthens an alternate cryptic 5' donor site in intron 12. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 246184 control chromosomes. c.1315+2T>C has been reported in the literature in individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria; Michiels_1998, Mirisola_2001, Trunzo_2015, Vela-Amieva_2015). These data indicate that the variant is likely to be associated with disease. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000088827 SCV000119419 not provided not provided no assertion provided not provided

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