ClinVar Miner

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

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Total submissions: 7
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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 (; 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 2020-02-14 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). 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.
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

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