ClinVar Miner

Submissions for variant NM_000325.6(PITX2):c.416G>C (p.Trp139Ser)

dbSNP: rs772800095
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000801898 SCV000941697 pathogenic Axenfeld-Rieger syndrome type 1; Anterior segment dysgenesis 4 2018-09-24 criteria provided, single submitter clinical testing 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 has been observed in individuals affected with Axenfeld-Rieger syndrome, in at least one of whom it was found de novo (PMID: 22569110, Invitae). This variant is not present in population databases (ExAC no frequency). This sequence change replaces tryptophan with serine at codon 86 of the PITX2 protein (p.Trp86Ser). The tryptophan residue is highly conserved and there is a large physicochemical difference between tryptophan and serine. For these reasons, this variant has been classified as Pathogenic. The observation of one or more missense substitutions at this codon (p.Trp86Ser and p.Trp86Cys) in affected individuals suggests that this may be a clinically significant residue (PMID: 19052653, 22569110).
Human Developmental Genetics Laboratory, Medical College of Wisconsin RCV002293482 SCV002538946 pathogenic Axenfeld-Rieger syndrome type 1 2022-06-23 criteria provided, single submitter research

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