ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.712A>C (p.Thr238Pro) (rs199475577)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000672442 SCV000797548 uncertain significance Phenylketonuria 2018-02-06 criteria provided, single submitter clinical testing
Invitae RCV000672442 SCV001236278 pathogenic Phenylketonuria 2019-11-26 criteria provided, single submitter clinical testing This sequence change replaces threonine with proline at codon 238 of the PAH protein (p.Thr238Pro). The threonine residue is highly 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 PKU (PMID: 1363786, 11295882). ClinVar contains an entry for this variant (Variation ID: 102796). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant disrupts the p.Thr238 amino acid residue in PAH. Other variant(s) that disrupt this residue have been observed in individuals with PAH-related conditions (PMID: 23690520), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000089047 SCV000119652 not provided not provided no assertion provided not provided

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