chr10-102230766-G-GCCCAGGCCCTGCAGGGC
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The NM_005029.4(PITX3):c.640_656dupGCCCTGCAGGGCCTGGG(p.Gly220ProfsTer95) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000736 in 1,358,438 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 7.4e-7 ( 0 hom. )
Consequence
PITX3
NM_005029.4 frameshift
NM_005029.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 2.31
Genes affected
PITX3 (HGNC:9006): (paired like homeodomain 3) This gene encodes a member of the RIEG/PITX homeobox family, which is in the bicoid class of homeodomain proteins. Members of this family act as transcription factors. This protein is involved in lens formation during eye development. Mutations of this gene have been associated with anterior segment mesenchymal dysgenesis and congenital cataracts. [provided by RefSeq, Jul 2008]
GBF1 (HGNC:4181): (golgi brefeldin A resistant guanine nucleotide exchange factor 1) This gene encodes a member of the Sec7 domain family. The encoded protein is a guanine nucleotide exchange factor that regulates the recruitment of proteins to membranes by mediating GDP to GTP exchange. The encoded protein is localized to the Golgi apparatus and plays a role in vesicular trafficking by activating ADP ribosylation factor 1. The encoded protein has also been identified as an important host factor for viral replication. Multiple transcript variants have been observed for this gene. [provided by RefSeq, Dec 2010]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 14 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.278 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 10-102230766-G-GCCCAGGCCCTGCAGGGC is Pathogenic according to our data. Variant chr10-102230766-G-GCCCAGGCCCTGCAGGGC is described in ClinVar as [Pathogenic]. Clinvar id is 468353.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| PITX3 | NM_005029.4 | c.640_656dupGCCCTGCAGGGCCTGGG | p.Gly220ProfsTer95 | frameshift_variant | Exon 4 of 4 | ENST00000370002.8 | NP_005020.1 | |
| PITX3 | XM_047425352.1 | c.640_656dupGCCCTGCAGGGCCTGGG | p.Gly220ProfsTer95 | frameshift_variant | Exon 3 of 3 | XP_047281308.1 | ||
| GBF1 | NM_001391923.1 | c.-149_-133dupCAGGGCCCCAGGCCCTG | 5_prime_UTR_variant | Exon 1 of 40 | NP_001378852.1 | |||
| GBF1 | NM_001391924.1 | c.-287_-271dupCAGGGCCCCAGGCCCTG | 5_prime_UTR_variant | Exon 1 of 41 | NP_001378853.1 |
Ensembl
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
33
GnomAD4 exome AF: 7.36e-7 AC: 1AN: 1358438Hom.: 0 Cov.: 32 AF XY: 0.00000149 AC XY: 1AN XY: 669420
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33
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:3
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | May 01, 2023 | PITX3: PP1:Strong, PM2, PVS1:Moderate, PP4, PS3:Supporting - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 26, 2025 | 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. This variant is not present in population databases (gnomAD no frequency). 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 gene product 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). For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 25, 2018 | 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. - |
ANTERIOR SEGMENT DYSGENESIS 1, MULTIPLE SUBTYPES Pathogenic:1
| Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 2008 | - - |
Cataract 11, posterior polar Pathogenic:1
| Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 2008 | - - |
Cataract 11 multiple types Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jun 15, 2023 | - - |
PITX3-related disorder Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Aug 12, 2024 | The PITX3 c.640_656dup17 variant is predicted to result in a frameshift and premature protein termination (p.Gly220Profs*95). This variant has been reported as causative for autosomal dominant congenital cataract and anterior segment malformations in multiple individuals (Verdin et al. 2014. PubMed ID: 24555714; Semina et al. 1998. PubMed ID: 9620774. Sakazume et al. 2007. PubMed ID: 17888164, reported as G219fs; Zhang et al. 2018. PubMed ID: 30078984). This variant has not been documented in a large population database, indicating this variant is rare. This variant has been classified as pathogenic by multiple independent submitters to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/468353). Given all the evidence, we interpret c.640_656dup (p.Gly220Profs*95) as pathogenic. - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at