Submissions for variant NM_000277.3(PAH):c.1315+6T>A

dbSNP: rs62508650

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000668481	SCV001250568	pathogenic	Phenylketonuria	2019-11-05	reviewed by expert panel	curation	This c.1315+6T>A (IVS12+6T>A) variant was documented three times in Southern Chinese patients and 5 times in Northern Chinese patients with PAH deficiency; DHPR activity, biopterin and/or pteridine analysis was performed to rule out other causes of hyperphenylalaninemia (PMID: 26503515). This variant was documented in at least 7 patients with PAH deficiency, with a pathogenic PAH variant in trans (PMID: 16256386, 23932990, 28982351). This variant is absent from the population databases ExAC and gnomAD. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PP4_moderate, PM3_very strong.
Counsyl	RCV000668481	SCV000793092	likely pathogenic	Phenylketonuria	2017-08-02	criteria provided, single submitter	clinical testing
Invitae	RCV000668481	SCV001579237	pathogenic	Phenylketonuria	2020-03-10	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Nucleotide substitutions within 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, but this prediction has not been confirmed by published transcriptional studies. This variant has been observed in several individuals affected with mild phenylketonuria or mild hyperphenylalaninemia (PMID: 16256386, 29731766, 23932990). This variant is also known as IVS12+6T>A in the literature. ClinVar contains an entry for this variant (Variation ID: 102590). This variant is not present in population databases (ExAC no frequency). This sequence change falls in intron 12 of the PAH gene. It does not directly change the encoded amino acid sequence of the PAH protein, but it affects a nucleotide within the consensus splice site of the intron.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000668481	SCV004020540	pathogenic	Phenylketonuria	2023-06-09	criteria provided, single submitter	clinical testing	Variant summary: PAH c.1315+6T>A alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Three predict the variant weakens the canonical 5' splice donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251404 control chromosomes. c.1315+6T>A has been reported in the literature in multiple individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) such as mild hyperphenylalaninaemia (MHP) or mild Phenyketonuria (mPKU) (example, Li_2018, Hillert_2020). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 32668217, 30050108). Two clinical diagnostic laboratories and the ClinGen PAH Variant Curation Expert Panel have submitted clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV000668481	SCV004209701	pathogenic	Phenylketonuria	2023-02-15	criteria provided, single submitter	clinical testing
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000088829	SCV000119421	not provided	not provided		no assertion provided	not provided