Genetic Variant PITX3:p.Gly220ProfsTer95 (chr10-102230766-G-GCCCAGGCCCTGCAGGGC) – ACMG Classification: Pathogenic (14 pts)

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

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 2.31

Variant links:

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]

PITX3 links:

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]

GBF1 links:

Genome browser will be placed here

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
PITX3	NM_005029.4 link	c.640_656dupGCCCTGCAGGGCCTGGG	p.Gly220ProfsTer95	frameshift_variant	Exon 4 of 4	ENST00000370002.8	NP_005020.1
PITX3	XM_047425352.1 link	c.640_656dupGCCCTGCAGGGCCTGGG	p.Gly220ProfsTer95	frameshift_variant	Exon 3 of 3		XP_047281308.1
GBF1	NM_001391923.1 link	c.-149_-133dupCAGGGCCCCAGGCCCTG		5_prime_UTR_variant	Exon 1 of 40		NP_001378852.1
GBF1	NM_001391924.1 link	c.-287_-271dupCAGGGCCCCAGGCCCTG		5_prime_UTR_variant	Exon 1 of 41		NP_001378853.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PITX3	ENST00000370002.8 link	c.640_656dupGCCCTGCAGGGCCTGGG	p.Gly220ProfsTer95	frameshift_variant	Exon 4 of 4	1	NM_005029.4	ENSP00000359019.3		O75364

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.36e-7

AC:

AN:

1358438

Hom.:

Cov.:

AF XY:

0.00000149

AC XY:

AN XY:

669420

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.40e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Oct 25, 2018

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

Jan 26, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. 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. -

May 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PITX3: PP1:Strong, PM2, PVS1:Moderate, PP4, PS3:Supporting -

ANTERIOR SEGMENT DYSGENESIS 1, MULTIPLE SUBTYPES

Pathogenic:1

Jan 01, 2008

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Cataract 11, posterior polar

Pathogenic:1

Jan 01, 2008

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Cataract 11 multiple types

Pathogenic:1

Jun 15, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

PITX3-related disorder

Pathogenic:1

Aug 12, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over