NM_000325.6:c.431G>C

Variant names:

• chr4-110618669-C-G
• rs104893859
• NM_000325.6:c.431G>C

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000325.6(PITX2):​c.431G>C​(p.Arg144Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R144Q) has been classified 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:3
• Conservation: PhyloP100: 7.57
• Publications: 6 publications found

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]

PITX2 Gene-Disease associations (from GenCC):

• anterior segment dysgenesis 4

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• Axenfeld-Rieger syndrome type 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• ring dermoid of cornea

  Inheritance: Unknown, AD Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet
• aniridia

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• Axenfeld anomaly

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Axenfeld-Rieger syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial atrial fibrillation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Rieger anomaly

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Peters anomaly

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_000325.6
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr4-110618669-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 197883.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.985
• PP5: Variant 4-110618669-C-G is Pathogenic according to our data. Variant chr4-110618669-C-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 8087.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-110618669-C-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 8087.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-110618669-C-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 8087.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-110618669-C-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 8087.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-110618669-C-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 8087.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-110618669-C-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 8087.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-110618669-C-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 8087.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-110618669-C-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 8087.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-110618669-C-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 8087.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-110618669-C-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 8087.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-110618669-C-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 8087.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-110618669-C-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 8087.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-110618669-C-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 8087.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-110618669-C-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 8087.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PITX2	NM_000325.6	c.431G>C	p.Arg144Pro	missense_variant	Exon 3 of 3	ENST00000644743.1	NP_000316.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PITX2	ENST00000644743.1	c.431G>C	p.Arg144Pro	missense_variant	Exon 3 of 3		NM_000325.6	ENSP00000495061.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Axenfeld-Rieger syndrome type 1 Pathogenic:2

Dec 01, 1996

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jun 23, 2022

Human Developmental Genetics Laboratory, Medical College of Wisconsin

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Inborn genetic diseases Pathogenic:1

Dec 13, 2018

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	35
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	.;.;D;D;.;D;D;D;.;D;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.97
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	.;D;.;.;.;.;.;D;D;D;D
M_CAP	Pathogenic	0.66	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Pathogenic	4.5	.;.;H;H;.;H;H;H;.;.;.
PhyloP100		7.6
PrimateAI	Pathogenic	0.94	D
PROVEAN	Pathogenic	-6.4	.;D;.;D;D;D;.;.;.;D;D
REVEL	Pathogenic	0.88
Sift	Uncertain	0.0010	.;D;.;D;D;D;.;.;.;D;D
Sift4G	Pathogenic	0.0010	.;D;.;D;D;D;D;D;D;D;.
Polyphen		1.0	D;D;D;D;D;D;D;D;D;.;.
Vest4		0.97, 0.97, 0.95, 0.96, 0.95
MutPred		0.90		.;.;Gain of methylation at K134 (P = 0.0707);Gain of methylation at K134 (P = 0.0707);.;Gain of methylation at K134 (P = 0.0707);Gain of methylation at K134 (P = 0.0707);Gain of methylation at K134 (P = 0.0707);.;Gain of methylation at K134 (P = 0.0707);.;
MVP		0.98
MPC		2.4
ClinPred		1.0	D
GERP RS		4.8
Varity_R		0.99
gMVP		1.0
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs104893859; hg19: chr4-111539825;