ClinGen Dosage Sensitivity Curation Page


Curation Status: Complete

Gene Information

Location Information

Evidence for Loss Phenotypes

Evidence for loss of function phenotype
PubMed ID Description
21285886 Raca et al. (2011) reported a 240 kb deletion encompassing the entire PAX2 coding region and a portion of the FAM178A (C20orf6) gene in a patient with renal-coloboma syndrome. This deletion was identified through array CGH. Follow-up testing with proband's parents were not performed.
11241473 Ford et al. (2001) reported a frameshift variant in exon 2 of the PAX2 gene (c.619insG; NM_003990.3 c.76dup; p.Val26Glyfs*28) in a family with renal-coloboma syndrome through targeted Sanger sequencing of the PAX2 gene. The frameshift variant was first identified in a proband (IV-7, Fig. 1) who presented prenatally with renal disease. Three affected family members spanning 3 generations from the proband (II-3, III-19, III-20, Fig. 1) were identified to have the c.619insC variant. Three non-affected family members (II-5, III-8, III-8, Fig. 1) were identified to not have the c.619insC variant.
22213154 Bower et al. (2012) within their review report 3 unrelated probands with renal-coloboma syndrome with de novo frameshift variants in PAX2 (Family 66, 73, 75; Supp Table S1) . Two unrelated probands with renal-coloboma syndrome with frameshift variants in PAX2 were reported in which one parent was affected and shared the same frameshift variant (Family 43, 68; Supp Table S1). Two unrelated probands with renal-coloboma were found to have frameshift variants in PAX2 (Family 62, 70; Supp Table 1), however follow-up testing with proband?s parents were not performed. Within the review by Bower et al. the authors reference additional studies of probands with renal-coloboma syndrome with either frameshift variants (15 reports) or nonsense variants (9 reports).

Evidence for Triplosenstive Phenotype

NOTE:The loss of function score should be used to evaluate deletions, and the triplosensitivity score should be used to evaluated duplications. CNVs encompassing more than one gene must be evaluated in their totality (e.g. overall size, gain vs. loss, presence of other genes, etc). The rating of a single gene within the CNV should not necessarily be the only criteria by which one defines a clinical interpretation. Individual interpretations must take into account the phenotype described for the patient as well as issues of penetrance and expressivity of the disorder. ACMG has published guidelines for the characterization of postnatal CNVs, and these recommendations should be utilized (Genet Med (2011)13: 680-685). Exceptions to these interpretive correlations will occur, and clinical judgment should always be exercised.