Submissions for variant NM_000277.3(PAH):c.842+5G>A

gnomAD frequency: 0.00002  dbSNP: rs62516146

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000169348	SCV000220717	likely pathogenic	Phenylketonuria	2014-09-23	criteria provided, single submitter	literature only
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000169348	SCV000221204	likely pathogenic	Phenylketonuria	2014-03-19	criteria provided, single submitter	clinical testing	The 842+5G>A variant in PAH has been reported in 1 German individual with PKU who was compound heterozygous for the pathogenic Arg408Trp variant (Guldberg 1996). This variant has also been identified in 1/8600 of European American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs62516146). This variant is located in the 5' splice region and is predicted to cause altered splicing leading to an abnormal or absent protein. Of note, several other variants at this splice region have been reported in individuals with PKU. In summary, this variant is likely pathogenic, though additional studies are required to fully establish its clinical significance.
GeneDx	RCV000089133	SCV000617702	pathogenic	not provided	2021-08-26	criteria provided, single submitter	clinical testing	Non-canonical splice site variant demonstrated to result in loss-of-function (Liang et al., 2014); Expression studies found that this variant is associated with less than 1% residual enzyme activity compared to wild-type (Liang et al., 2014); Not observed at significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 24401910, 17935162, 27535533, 32668217, 29499199, 25466353, 8889590, 25525159)
Invitae	RCV000169348	SCV000834426	pathogenic	Phenylketonuria	2023-08-08	criteria provided, single submitter	clinical testing	This sequence change falls in intron 7 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 present in population databases (rs62516146, gnomAD 0.01%). This variant has been observed in individuals with phenylalanine hydroxylase deficiency (PMID: 8889590, 17502162, 19609714, 23932990, 24401910). This variant is also known as IVS7+5G>A. ClinVar contains an entry for this variant (Variation ID: 102872). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 24401910). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000169348	SCV001437259	pathogenic	Phenylketonuria	2020-09-24	criteria provided, single submitter	clinical testing	Variant summary: PAH c.842+5G>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: Four predict the variant abolishes the canonical 5' splicing donor site thereby predicting intron retention. At least one publication reports experimental evidence that this variant affects mRNA splicing by a similar mechanism (Liang_2014). The variant allele was found at a frequency of 4e-06 in 251264 control chromosomes. c.842+5G>A has been reported in the literature in individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (example, Guldberg_1996, Dobrowlski_2007, Langenbeck_2009, Zhu_2013, Liang_2014). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in an absence of normal activity in transfected COS-1 cells (Liang_2014). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV000169348	SCV004201349	pathogenic	Phenylketonuria	2023-10-22	criteria provided, single submitter	clinical testing
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000089133	SCV000119743	not provided	not provided		no assertion provided	not provided
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000089133	SCV001931508	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000089133	SCV001965994	pathogenic	not provided		no assertion criteria provided	clinical testing