rs104893862

Variant names:

• chr4-110621231-C-T
• rs104893862
• NM_000325.6:c.344G>A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PP3_Moderate PP5_Very_Strong

The NM_000325.6(PITX2):​c.344G>A​(p.Arg115His) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: PITX2 NM_000325.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 6.10

Genes affected

PITX2 (HGNC:9005): (paired like homeodomain 2) This gene encodes a member of the RIEG/PITX homeobox family, which is in the bicoid class of homeodomain proteins. The encoded protein acts as a transcription factor and regulates procollagen lysyl hydroxylase gene expression. This protein plays a role in the terminal differentiation of somatotroph and lactotroph cell phenotypes, is involved in the development of the eye, tooth and abdominal organs, and acts as a transcriptional regulator involved in basal and hormone-regulated activity of prolactin. Mutations in this gene are associated with Axenfeld-Rieger syndrome, iridogoniodysgenesis syndrome, and sporadic cases of Peters anomaly. A similar protein in other vertebrates is involved in the determination of left-right asymmetry during development. Alternatively spliced transcript variants encoding distinct isoforms have been described. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM1: In a DNA_binding_region Homeobox (size 59) in uniprot entity PITX2_HUMAN there are 15 pathogenic changes around while only 0 benign (100%) in NM_000325.6
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.884
• PP5: Variant 4-110621231-C-T is Pathogenic according to our data. Variant chr4-110621231-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 8094.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-110621231-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PITX2	NM_000325.6	c.344G>A	p.Arg115His	missense_variant	Exon 2 of 3	ENST00000644743.1	NP_000316.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PITX2	ENST00000644743.1	c.344G>A	p.Arg115His	missense_variant	Exon 2 of 3		NM_000325.6	ENSP00000495061.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Anterior segment dysgenesis Pathogenic:1

Mar 31, 2020

Eye Genetics Research Group, Children's Medical Research Institute

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Ring dermoid of cornea Pathogenic:1

Dec 01, 2004

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Inborn genetic diseases Pathogenic:1

Apr 11, 2023

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.185G>A (p.R62H) alteration is located in exon 4 (coding exon 2) of the PITX2 gene. This alteration results from a G to A substitution at nucleotide position 185, causing the arginine (R) at amino acid position 62 to be replaced by a histidine (H). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration was reported in multiple individuals or families with clinical features of PITX2-related Axenfeld-Rieger syndrome (Xia, 2004; Reis, 2012; Ma, 2020). This amino acid position is highly conserved in available vertebrate species. The p.R62H amino acid is located in the homeodomain. Molecular modeling predicted this alteration would have minor or no impact on the structure of PITX2 (Seifi, 2018). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic. -

Axenfeld-Rieger syndrome type 1 Pathogenic:1

Jun 23, 2022

Human Developmental Genetics Laboratory, Medical College of Wisconsin

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Anterior segment dysgenesis 4;C3714873:Axenfeld-Rieger syndrome type 1 Pathogenic:1

Mar 03, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 62 of the PITX2 protein (p.Arg62His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Axenfeld-Rieger syndrome, peripheral sclerocornea, and/or ring dermoid of cornea (PMID: 15591271, 22569110, 32499604). It has also been observed to segregate with disease in related individuals. This variant is also known as R24H and R108H. ClinVar contains an entry for this variant (Variation ID: 8094). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Experimental studies have shown that this missense change affects PITX2 function (PMID: 21052876, 22224469, 27013732). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.95	.;.;D;D;.;D;D;D;.;D;.;.
Eigen	Benign	0.011
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.90	.;D;.;.;.;.;.;D;D;D;D;D
M_CAP	Pathogenic	0.49	D
MetaRNN	Pathogenic	0.88	D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.14	D
MutationAssessor	Benign	0.010	.;.;N;N;.;N;N;N;.;.;.;.
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-4.7	.;D;.;D;D;D;.;.;.;D;D;.
REVEL	Pathogenic	0.76
Sift	Pathogenic	0.0	.;D;.;D;D;D;.;.;.;T;T;.
Sift4G	Pathogenic	0.0	.;D;.;T;T;T;T;T;T;T;.;T
Polyphen		0.99	D;D;D;D;D;D;D;D;D;D;.;.
Vest4		0.49, 0.50, 0.47, 0.50, 0.47, 0.46
MutPred		0.73		.;.;Gain of glycosylation at S113 (P = 0.0316);Gain of glycosylation at S113 (P = 0.0316);.;Gain of glycosylation at S113 (P = 0.0316);Gain of glycosylation at S113 (P = 0.0316);Gain of glycosylation at S113 (P = 0.0316);.;Gain of glycosylation at S113 (P = 0.0316);.;.;
MVP		0.98
MPC		1.3
ClinPred		1.0	D
GERP RS		4.5
Varity_R		0.84
gMVP		0.87

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs104893862; hg19: chr4-111542387;