Submissions for variant NM_000325.6(PITX2):c.448_449del (p.Arg150fs)

dbSNP: rs2110432091

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001956173	SCV002237516	pathogenic	Axenfeld-Rieger syndrome type 1; Anterior segment dysgenesis 4	2021-09-18	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg97Glyfs*101) in the PITX2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 175 amino acid(s) of the PITX2 protein. For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the PITX2 protein in which other variant(s) (p.Trp133*) have been determined to be pathogenic (PMID: 8944018, 16498627). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. This premature translational stop signal has been observed in individual(s) with clinical features of PITX2-related conditions (PMID: 22569110). This variant is not present in population databases (ExAC no frequency).
Human Developmental Genetics Laboratory, Medical College of Wisconsin	RCV002293544	SCV002538932	pathogenic	Axenfeld-Rieger syndrome type 1	2022-06-23	criteria provided, single submitter	research
Ambry Genetics	RCV004044391	SCV005004166	pathogenic	Inborn genetic diseases	2024-03-01	criteria provided, single submitter	clinical testing	The c.289_290delAG (p.R97Gfs*101) alteration, located in exon 5 (coding exon 3) of the PITX2 gene, consists of a deletion of 2 nucleotides from position 289 to 290, causing a translational frameshift with a predicted alternate stop codon after 101 amino acids. This alteration occurs in the last exon of the PITX2 gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 65% of the protein. Premature stop codons are typically deleterious in nature and a significant portion of the protein is affected (Ambry internal data). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant was reported in an individual with features consistent with PITX2-related Axenfeld-Rieger syndrome (Reis, 2012). Based on the available evidence, this alteration is classified as pathogenic.