ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.1037G>A (p.Gly346Glu) (rs1555203737)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000553622 SCV000629167 uncertain significance Phenylketonuria 2017-04-27 criteria provided, single submitter clinical testing This sequence change replaces glycine with glutamic acid at codon 346 of the PAH protein (p.Gly346Glu). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and glutamic acid. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with hyperphenylalaninemia (PMID: 19394257). In addition, different variants affecting the same codon, c.1036G>A and c.1036G>C, resulting in the p.Gly346Arg change have been reported in patients affected with classic PKU (PMID: 16256386). 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. In summary, this variant is a rare missense change with uncertain impact on protein function. While it is absent from the population and reported in affected individuals, the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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