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
Consequence
NM_005029.4 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
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 Cov.: 33
GnomAD4 exome AF: 7.36e-7 AC: 1AN: 1358438Hom.: 0 Cov.: 32 AF XY: 0.00000149 AC XY: 1AN XY: 669420
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
not provided Pathogenic:3
PITX3: PP1:Strong, PM2, PVS1:Moderate, PP4, PS3:Supporting -
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. -
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
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Cataract 11, posterior polar Pathogenic:1
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Cataract 11 multiple types Pathogenic:1
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PITX3-related disorder Pathogenic:1
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
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at