NM_000325.6(PITX2):c.208A>T (p.Lys70Ter) AND Axenfeld-Rieger syndrome type 1

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Jan 20, 2022
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV001825120.2

Allele description [Variation Report for NM_000325.6(PITX2):c.208A>T (p.Lys70Ter)]

NM_000325.6(PITX2):c.208A>T (p.Lys70Ter)

Gene:

PITX2:paired like homeodomain 2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

4q25

Genomic location:

Preferred name:

NM_000325.6(PITX2):c.208A>T (p.Lys70Ter)

HGVS:

NC_000004.12:g.110621367T>A
NG_007120.1:g.20986A>T
NM_000325.6:c.208A>TMANE SELECT
NM_001204397.2:c.187A>T
NM_001204398.1:c.187A>T
NM_001204399.1:c.49A>T
NM_153426.3:c.187A>T
NM_153427.3:c.49A>T
NP_000316.2:p.Lys70Ter
NP_001191326.1:p.Lys63Ter
NP_001191327.1:p.Lys63Ter
NP_001191328.1:p.Lys17Ter
NP_700475.1:p.Lys63Ter
NP_700476.1:p.Lys17Ter
NP_700476.1:p.Lys17Ter
NC_000004.11:g.111542523T>A
NM_153427.2:c.49A>T

Protein change:

K17*

Links:

dbSNP: rs2110435882

NCBI 1000 Genomes Browser:

rs2110435882

Molecular consequence:

NM_000325.6:c.208A>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001204397.2:c.187A>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001204398.1:c.187A>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001204399.1:c.49A>T - nonsense - [Sequence Ontology: SO:0001587]
NM_153426.3:c.187A>T - nonsense - [Sequence Ontology: SO:0001587]
NM_153427.3:c.49A>T - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Name:: Axenfeld-Rieger syndrome type 1 (RIEG1)
Synonyms:: Rieger syndrome type 1
Identifiers:: MONDO: MONDO:0008386; MedGen: C3714873; Orphanet: 782; OMIM: 180500

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002074381	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (Jan 20, 2022)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002074381

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely pathogenic
(Jan 20, 2022)

germline

clinical testing

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002074381.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

Variant summary: PITX2 c.49A>T (p.Lys17X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been associated with Axenfeld-Rieger syndrome in HGMD. 4/4 computational tools predict no significant impact on normal splicing acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 250440 control chromosomes (gnomAD). To our knowledge, no occurrence of c.49A>T in individuals affected with Axenfeld-Rieger Syndrome Type 1 and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Dec 24, 2023

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