ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.941C>A (p.Pro314His) (rs62642940)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000409567 SCV000486619 likely pathogenic Phenylketonuria 2016-07-12 criteria provided, single submitter clinical testing
Genome Diagnostics Laboratory,University Medical Center Utrecht RCV000409567 SCV000744093 pathogenic Phenylketonuria 2014-10-08 criteria provided, single submitter clinical testing
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000409567 SCV000745571 likely pathogenic Phenylketonuria 2016-01-04 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000409567 SCV001363421 pathogenic Phenylketonuria 2019-08-29 criteria provided, single submitter clinical testing Variant summary: PAH c.941C>A (p.Pro314His) results in a non-conservative amino acid change located in the catalytic domain (IPR041912) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251290 control chromosomes (gnomAD). c.941C>A has been reported in the literature in multiple individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (e.g. Guldberg_1998, Anjema_2013, Vela-Amieva_2015). These data indicate that the variant is very likely to be associated with disease. A publication reported experimental evidence using an in vitro expression system, and demonstrated that the variant significantly reduced enzyme activity, as well as (in addition to its protein level effects) it also increased exon 9 skipping by disrupting exonic splicing enhancer (ESE) motifs (Ho_2008). Two ClinVar submissions (evaluation after 2014) cite the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000409567 SCV001414760 pathogenic Phenylketonuria 2019-11-05 criteria provided, single submitter clinical testing This sequence change replaces proline with histidine at codon 314 of the PAH protein (p.Pro314His). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and histidine. This variant is not present in population databases (ExAC no frequency). This variant has been observed combination with another PAH variant in an individual affected with phenylketonuria (PKU) (PMID: 8807319). ClinVar contains an entry for this variant (Variation ID: 102907). This variant has been reported to affect PAH protein function (PMID: 18590700). Experimental studies have shown that this variant disrupts mRNA splicing (PMID: 18590700). This variant disrupts the p.Pro314 amino acid residue in PAH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 28982351, 24401910, 29390883). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000089171 SCV000119786 not provided not provided no assertion provided not provided

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