NM_005029.4:c.640_656delGCCCTGCAGGGCCTGGG

Variant names:

• chr10-102230766-GCCCAGGCCCTGCAGGGC-G
• rs1411557416
• NM_005029.4:c.640_656delGCCCTGCAGGGCCTGGG

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 12P and 4B. PVS1_Strong PP5_Very_Strong BS2

The NM_005029.4(PITX3):​c.640_656delGCCCTGCAGGGCCTGGG​(p.Ala214ArgfsTer42) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000397 in 1,510,390 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000041 (0 hom.)
• Consequence: PITX3 NM_005029.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 6.70

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 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 0.296 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
• PP5: Variant 10-102230766-GCCCAGGCCCTGCAGGGC-G is Pathogenic according to our data. Variant chr10-102230766-GCCCAGGCCCTGCAGGGC-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 468252.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-102230766-GCCCAGGCCCTGCAGGGC-G is described in Lovd as [Likely_pathogenic]. Variant chr10-102230766-GCCCAGGCCCTGCAGGGC-G is described in Lovd as [Pathogenic]. Variant chr10-102230766-GCCCAGGCCCTGCAGGGC-G is described in Lovd as [Pathogenic]. Variant chr10-102230766-GCCCAGGCCCTGCAGGGC-G is described in Lovd as [Pathogenic]. Variant chr10-102230766-GCCCAGGCCCTGCAGGGC-G is described in Lovd as [Likely_pathogenic]. Variant chr10-102230766-GCCCAGGCCCTGCAGGGC-G is described in Lovd as [Pathogenic].
• BS2: High AC in GnomAdExome4 at 56 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PITX3	NM_005029.4	c.640_656delGCCCTGCAGGGCCTGGG	p.Ala214ArgfsTer42	frameshift_variant	Exon 4 of 4	ENST00000370002.8	NP_005020.1
PITX3	XM_047425352.1	c.640_656delGCCCTGCAGGGCCTGGG	p.Ala214ArgfsTer42	frameshift_variant	Exon 3 of 3		XP_047281308.1
GBF1	NM_001391923.1	c.-149_-133delCAGGGCCCCAGGCCCTG		5_prime_UTR_variant	Exon 1 of 40		NP_001378852.1
GBF1	NM_001391924.1	c.-287_-271delCAGGGCCCCAGGCCCTG		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	c.640_656delGCCCTGCAGGGCCTGGG	p.Ala214ArgfsTer42	frameshift_variant	Exon 4 of 4	1	NM_005029.4	ENSP00000359019.3

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 151964 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000747 AC: 8 AN: 107136 Hom.: 0 AF XY: 0.000118 AC XY: 7 AN XY: 59242

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000564

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000138

Gnomad SAS exome AF: 0.000114

Gnomad FIN exome AF: 0.0000699

Gnomad NFE exome AF: 0.0000775

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000412 AC: 56 AN: 1358426 Hom.: 0 AF XY: 0.0000433 AC XY: 29 AN XY: 669416

Gnomad4 AFR exome AF: 0.0000720

Gnomad4 AMR exome AF: 0.000138

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000607

Gnomad4 SAS exome AF: 0.0000405

Gnomad4 FIN exome AF: 0.0000637

Gnomad4 NFE exome AF: 0.0000376

Gnomad4 OTH exome AF: 0.0000357

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 151964 Hom.: 0 Cov.: 33 AF XY: 0.0000404 AC XY: 3 AN XY: 74220

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000175 Hom.: 0

Bravo AF: 0.0000416

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cataract 11 multiple types Pathogenic:1

Jan 19, 2024

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1

Jul 21, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Experimental studies have shown that this premature translational stop signal affects PITX3 function (PMID: 30816539). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. This sequence change creates a premature translational stop signal (p.Ala214Argfs*42) in the PITX3 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 89 amino acid(s) of the PITX3 protein. This variant is present in population databases (no rsID available, gnomAD 0.01%). This premature translational stop signal has been observed in individuals with congenital cataracts and/or Peter's anomalies (PMID: 30816539; Invitae). ClinVar contains an entry for this variant (Variation ID: 468252). -

Anterior segment dysgenesis 1 Pathogenic:1

Mar 31, 2022

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with PITX3-related anterior segment dysgenesis and cataracts. (I) 0108 - This gene is associated with both recessive and dominant disease. This gene has mostly been associated with dominant disease, although rare cases of recessive inheritance have been reported, with homozygous individuals having a more severe phenotype (PMID: 21836522, PMID: 30816539, PMID: 29405783). (I) 0112 - The condition associated with this gene has incomplete penetrance (PMID: 30816539). (I) 0115 - Variants in this gene are known to have variable expressivity. A wide range of interfamilial and intrafamilial phenotypic variability has been reported. (PMID: 29405783). (I) 0205 - Variant is predicted to result in a truncated protein (premature termination codon is NOT located at least 54 nucleotides upstream of the final exon-exon junction) with less than 1/3 of the protein sequence affected. (SP) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 (8 heterozygotes, 0 homozygotes). (SP) 0600 - Variant is predicted to lose the OAR domain. The majority of reported pathogenic variants in PITX3 are predicted to result in the disruption of the OAR domain (PMID: 30894134). (I) 0702 - Other variants predicted to result in a truncated protein comparable to the one identified in this case have strong previous evidence for pathogenicity (ClinVar, PMID: 32830442). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. The variant has been previously reported in a homozygous patient with anterior segment dysgenesis and microphthalmia (PMID: 21836522) and heterozygous in at least four unrelated patients with congenital cataracts or Peters Anomaly (PMID: 30816539, PMID: 31848469, PMID: 33923544, PMID: 33304895). This variant has also been reported as a VUS in ClinVar. (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Functional studies indicated that the mutant protein retained a nuclear localisation pattern but resulted in decreased transactivation activity (PMID: 30816539). (SP) 1206 - This variant has been shown to be paternally inherited. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

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;