Total submissions: 6
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000627511 | SCV000748511 | pathogenic | not provided | 2018-10-25 | criteria provided, single submitter | clinical testing | The c.640_656dup17 variant in the PITX3 gene is the most common PITX3 pathogenic variant and has been reported to segregate with ocular disorders in multiple unrelated families (Semina et al., 1998; Verdin et al., 2014; Zazo Seco et al., 2018). The c.640_656dup17 variant causes a frameshift starting with codon Glycine 220, changes this amino acid to a Proline residue, and creates a premature Stop codon at position 95 of the new reading frame, denoted p.Gly220ProfsX95. This frameshift variant replaces the typical last 83 amino acid residues in the PITX3 protein with 94 different amino acid residues. Functional studies of eye cells transfected with the c.640_656dup17 variant (described as G219fs due to alternative nomenclature) demonstrated a decrease in the transactivation activity of the PITX3 protein compared to wild-type cells (Sakazume et al., 2007). Additional functional studies suggested that this variant impairs PITX3-DNA binding (Sakazume et al., 2007). The c.640_656dup17 variant is not observed in large population cohorts (Lek et al., 2016). We interpret c.640_656dup17 as a pathogenic variant. |
| Invitae | RCV000627511 | SCV001584894 | pathogenic | not provided | 2021-10-25 | criteria provided, single submitter | clinical testing | This sequence change results in a frameshift in the PITX3 gene (p.Gly220Profs*95). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 83 amino acid(s) of the PITX3 protein and extend the protein by 11 additional amino acid residues. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This frameshift has been observed in individuals with congenital cataracts (PMID: 9620774, 15286169, 24555714, 29405783). It has also been observed to segregate with disease in related individuals. This variant is also known as 657ins17. ClinVar contains an entry for this variant (Variation ID: 468353). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this frameshift affects PITX3 function (PMID: 17888164, 24555714). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic. |
| Ce |
RCV000627511 | SCV002585250 | pathogenic | not provided | 2023-05-01 | criteria provided, single submitter | clinical testing | PITX3: PP1:Strong, PM2, PVS1:Moderate, PP4, PS3:Supporting |
| Baylor Genetics | RCV003333078 | SCV004041113 | pathogenic | Cataract 11 multiple types | 2023-06-15 | criteria provided, single submitter | clinical testing | |
| OMIM | RCV002294347 | SCV000027547 | pathogenic | ANTERIOR SEGMENT DYSGENESIS 1, MULTIPLE SUBTYPES | 2008-01-01 | no assertion criteria provided | literature only | |
| OMIM | RCV002294346 | SCV000071246 | pathogenic | Cataract 11, posterior polar | 2008-01-01 | no assertion criteria provided | literature only |