ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.385G>T (p.Asp129Tyr) (rs199475606)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000088907 SCV000239050 pathogenic not provided 2015-03-17 criteria provided, single submitter clinical testing The D129Y missense mutation in the PAH gene has been reported as a pathogenic mutation in the PAH Consortium database. The variant is found in PAH panel(s).
Invitae RCV000811501 SCV000951769 likely pathogenic Phenylketonuria 2019-10-29 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with tyrosine at codon 129 of the PAH protein (p.Asp129Tyr). The aspartic acid residue is highly conserved and there is a large physicochemical difference between aspartic acid and tyrosine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals with phenylketonuria (PMID: 26542770, Invitae). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 102660). 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. 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 RCV000088907 SCV000119505 not provided not provided no assertion provided not provided

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