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

dbSNP: rs62508650

Total submissions: 8

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
Labcorp Genetics (formerly Invitae), Labcorp	RCV000668481	SCV001579237	pathogenic	Phenylketonuria	2024-12-23	criteria provided, single submitter	clinical testing	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. It affects a nucleotide within the consensus splice site. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with mild phenylketonuria or mild hyperphenylalaninemia (PMID: 16256386, 23932990, 29731766). This variant is also known as IVS12+6T>A. ClinVar contains an entry for this variant (Variation ID: 102590). 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. For these reasons, this variant has been classified as Pathogenic.
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	2024-02-28	criteria provided, single submitter	clinical testing
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV000668481	SCV005418322	pathogenic	Phenylketonuria		criteria provided, single submitter	clinical testing	PM2_Supporting+PM3_VeryStrong+PP3+PP4
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000088829	SCV000119421	not provided	not provided		no assertion provided	not provided
PreventionGenetics, part of Exact Sciences	RCV004724807	SCV005336388	pathogenic	PAH-related disorder	2024-08-06	no assertion criteria provided	clinical testing	The PAH c.1315+6T>A variant is predicted to interfere with splicing. This variant is also referred to as IVS12+6T>A in the literature. This variant has been reported with a second PAH variant in individuals with mild phenylketonuria or hyperphenylalaninemia (see, for example, Song et al. 2005. PubMed ID: 16256386; Table S2, Li et al. 2018. PubMed ID: 30050108; Supplementary Table 2, Zeng et al. 2023. PubMed ID: 36845377). This variant is predicted to alter splicing based on available splicing prediction programs (SpliceAI, Jaganathan et al. 2019. PubMed ID: 30661751). However, the use of computer prediction programs is not equivalent to functional evidence. This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic or likely pathogenic in ClinVar, including by the ClinGen PAH Variant Curation Expert Panel (https://www.ncbi.nlm.nih.gov/clinvar/variation/102590/). This variant is interpreted as pathogenic.