ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.842+5G>A (rs62516146)

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Total submissions: 5
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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, Partners HealthCare 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 2018-07-27 criteria provided, single submitter clinical testing The c.842+5 G>A splice site variant has been reported in association with classic phenylketonuria (PKU) (Liang et al. 2014). In COS-1 cells transfected with the c.842+5 G>A variant, splicing was completely abolished and residual phenylalanine hydroxylase activity was less than 1% compared to wild-type (Liang et al. 2014). It is unclear whether or not the c.842+5 G>A variant is responsive to tetrahydrobiopterin (BH4) therapy (Zurfluh et al. 2008).
Invitae RCV000169348 SCV000834426 pathogenic Phenylketonuria 2019-03-20 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, but it affects a nucleotide within the consensus splice site of the intron. This variant is present in population databases (rs62516146, ExAC 0.001%). This variant has been reported with a second heterozygous variant in the PAH gene in multiple individuals with phenylalanine hydroxylase deficiency (PMID: 8889590, 17502162, 19609714, 23932990, 24401910). It is also known as IVS7+5G>A in the literature. ClinVar contains an entry for this variant (Variation ID: 102872). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this intronic variant results in intron retention in a cell culture splicing assay (PMID: 24401910). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000089133 SCV000119743 not provided not provided no assertion provided not provided

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