ClinVar Miner

Submissions for variant NM_000325.6(PITX2):c.430C>T (p.Arg144Trp)

dbSNP: rs1057519485
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001379880 SCV001577765 likely pathogenic Axenfeld-Rieger syndrome type 1; Anterior segment dysgenesis 4 2020-05-06 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 91 of the PITX2 protein (p.Arg91Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with Axenfeld-Rieger syndrome (PMID: 29506241). It has also been observed to segregate with disease in related individuals. 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.Arg91 amino acid residue in PITX2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8944018, 12130547). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.
Human Developmental Genetics Laboratory, Medical College of Wisconsin RCV002293534 SCV002538950 likely pathogenic Axenfeld-Rieger syndrome type 1 2022-06-23 criteria provided, single submitter research
GeneDx RCV004720887 SCV005326617 likely pathogenic not provided 2023-10-09 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29506241)

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