ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.241A>C (p.Thr81Pro) (rs62509017)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000088881 SCV001134523 pathogenic not provided 2018-10-30 criteria provided, single submitter clinical testing Not found in the total gnomAD dataset, and the data are high quality. Statistically enriched in patients compared to controls. Predicted to have a damaging effect on the protein. Occurs in multiple cases with a recessive pathogenic variant in the same gene.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001192889 SCV001361329 likely pathogenic Phenylketonuria 2019-10-31 criteria provided, single submitter clinical testing Variant summary: PAH c.241A>C (p.Thr81Pro) results in a non-conservative amino acid change located in the ACT domain (IPR002912) 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 251436 control chromosomes (gnomAD). c.241A>C has been reported in the literature in individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (Guldberg_1996, Sarkissian_2012, Enns_1999). These data indicate that the variant is likely to be associated with disease. Another variant affecting the same codon (c.242C>A, p.T81N) has been classified as likely pathogenic in ClinVar by the ClinGen PAH Variant Curation Expert Panel (Variation ID: 208180). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Invitae RCV001192889 SCV001414753 pathogenic Phenylketonuria 2020-10-02 criteria provided, single submitter clinical testing This sequence change replaces threonine with proline at codon 81 of the PAH protein (p.Thr81Pro). The threonine residue is weakly conserved and there is a small physicochemical difference between threonine and proline. This variant is not present in population databases (ExAC no frequency). This variant has been observed in combination with another PAH variant in individuals affected with phenylketonuria (PMID: 8659548, 23430918). ClinVar contains an entry for this variant (Variation ID: 102637). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Benign; Align-GVGD: Class C0). For these reasons, this variant has been classified as Pathogenic.
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000088881 SCV000119478 not provided not provided no assertion provided not provided

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