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

dbSNP: rs1799970

Total submissions: 7

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.
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.
Myriad Genetics, Inc.	RCV000169029	SCV002060280	pathogenic	Phenylketonuria	2021-11-11	criteria provided, single submitter	clinical testing	NM_000277.1(PAH):c.1315+2T>C is a canonical splice variant classified as pathogenic in the context of phenylalanine hydroxylase deficiency. Please note that the c.1315+2T>C variant can be associated with classic or variant PKU. c.1315+2T>C has been observed in cases with relevant disease (PMID: 9521426, 9452062, 26210745, 31640267, 33564846, 32668217). Functional assessments of this variant are not available in the literature. c.1315+2T>C has not been observed in population frequency databases. In summary, NM_000277.1(PAH):c.1315+2T>C is a canonical splice variant that has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Fulgent Genetics, Fulgent Genetics	RCV000169029	SCV002793225	pathogenic	Phenylketonuria	2022-03-18	criteria provided, single submitter	clinical testing
Invitae	RCV000169029	SCV003440999	pathogenic	Phenylketonuria	2022-02-02	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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: 102588). This variant is also known as IVS12+2T>C. Disruption of this splice site has been observed in individuals with phenylketonuria (PMID: 9452062, 9521426, 24941924, 26210745, 32668217). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 12 of the PAH gene. While this variant is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product.
Baylor Genetics	RCV000169029	SCV004209641	pathogenic	Phenylketonuria	2023-07-11	criteria provided, single submitter	clinical testing
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000088827	SCV000119419	not provided	not provided		no assertion provided	not provided