ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000022.10) (NC_000022.11)
  • Haploinsufficiency score: 1
  • Strength of Evidence (disclaimer): Little evidence for dosage pathogenicity
Evidence for haploinsufficiency phenotype
PubMed ID Description
28121514 Lopez-Rivera et al. (2017) report sequence level variants in five individuals with renal agenesis or hypodysplasia. One of these variants was a nonsense variant (c.91C>T; NM_005207.3), which resulted in a premature termination of the transcript. The other four were missense variants that are evolutionarily conserved and rare/absent in control databases. Inheritance testing was not noted for these variants. Functional studies using a mouse knockout model was consistent with the CRKL gene being involved in renal development, with knockout mice showing developmental anomalies in the kidney and urinary tract including hydronephrosis. Of note, this paper also reported several patients with non-focal deletions overlapping the CRKL gene, who also had renal abnormalities.

Haploinsufficiency phenotype comments:

CRKL lies within the common 22q11.2 deletion syndrome region. Observations in mouse models have led to the hypothesis that haploinsufficiency of CRKL contributes to the 22q11.2 phenotype, particularly in regards to cardiovascular and genitourinary defects (PMID:16399079; 28121514). The single reported loss-of-function type variant (nonsense) in CRKL was identified in a patient who presented with renal hypodysplasia. Four additional missense variants have also been reported, but there is insufficient evidence to support that these are clinically causative, would result in a loss of CRKL protein function, or would be equivalent to loss of the entire copy of CRKL. Given the limited number of reported variants affecting the CRKL gene, the haploinsufficiency score for this gene is a 1.

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity

Triplosensitivity phenotype comment:

Focal duplications involving only CRKL have not been reported in the literature; therefore, the triplosensitivity score for this gene is a 0.