10-102230766-G-GCCCAGGCCCTGCAGGGC

Position:

• chr10-102230766-G-GCCCAGGCCCTGCAGGGC

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The ENST00000370002.8(PITX3):​c.656_657insGCCCTGCAGGGCCTGGG​(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 ENST00000370002.8 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• 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:):

ACMG classification

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. There are 4 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/exons	MANE	Protein	UniProt
PITX3	NM_005029.4	c.656_657insGCCCTGCAGGGCCTGGG	p.Gly220ProfsTer95	frameshift_variant	4/4	ENST00000370002.8	NP_005020.1
PITX3	XM_047425352.1	c.656_657insGCCCTGCAGGGCCTGGG	p.Gly220ProfsTer95	frameshift_variant	3/3		XP_047281308.1
GBF1	NM_001391923.1	c.-149_-133dup		5_prime_UTR_variant	1/40		NP_001378852.1
GBF1	NM_001391924.1	c.-287_-271dup		5_prime_UTR_variant	1/41		NP_001378853.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PITX3	ENST00000370002.8	c.656_657insGCCCTGCAGGGCCTGGG	p.Gly220ProfsTer95	frameshift_variant	4/4	1	NM_005029.4	ENSP00000359019	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.36e-7 AC: 1 AN: 1358438 Hom.: 0 Cov.: 32 AF XY: 0.00000149 AC XY: 1 AN XY: 669420

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.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 25, 2021	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. -
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. -
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 -

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

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1411557416; hg19: chr10-103990523;