ClinVar Miner

Submissions for variant NM_005029.4(PITX3):c.640_656dup (p.Gly220fs) (rs1411557416)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000547813 SCV000644964 pathogenic Anterior segment dysgenesis 1; Cataract 11 2018-11-27 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal 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 82 amino acids and extend the length of the PITX3 protein by 12 additional amino acid residues.1 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 variant has been observed to segregate with congenital cataracts in families (PMID: 9620774, 15286169, 24555714, 29405783). The variant is also known as 657ins17 in the literature. ClinVar contains an entry for this variant (Variation ID: 468353). This variant has been reported to affect PITX3 protein function (PMID: 24555714, 17888164). For these reasons, this variant has been classified as Pathogenic.
GeneDx 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 2020-02-03 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal 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 82 amino acids and extend the length of the PITX3 protein by 12 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 variant has been observed to segregate with congenital cataracts in families (PMID: 9620774, 15286169, 24555714, 29405783). The variant is also known as 657ins17 in the literature. ClinVar contains an entry for this variant (Variation ID: 468353). This variant has been reported to affect PITX3 protein function (PMID: 24555714, 17888164). For these reasons, this variant has been classified as Pathogenic.

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