ClinGen Dosage Sensitivity Curation Page

AVPR2

  • Curation Status: Complete

Location Information

Select assembly: (NC_000023.10) (NC_000023.11)
Evidence for haploinsufficiency phenotype
PubMed ID Description
10820168 Arthus et al. 2000 performed full gene sequencing on 117 families with nephrogenic diabetes insipidus (NDI) and identified 82 different variants in the AVPR2 gene (40 missense, 10 nonsense, 24 deletions, 7 insertions, and 1 splice-site). At least four of the patients were found to have de novo truncating variants.
23150186 Sasaki et al. (2013) performed full gene sequencing for AVPR2 and AQP2 in 78 Japanese families with NDI, 62 families of which were newly described in this paper (the 16 remaining families were described in prior publications). A total of 52 unique AVPR2 variants (28 missense, 4 nonsense, 13 deletions, 5 insertions, and 2 splicing) were identified in these 62 newly described families. While specific details are not provided for all families, at least some of the affected males inherited the AVPR2 variant from a symptomatic mother providing some of evidence of segregation for the variants.
29594432 Joshi et al. (2018) performed bi-directional sequencing of the coding regions of AVPR2 on 19 families with NDI and identified 16 unique AVPR2 variants. Of the 16 AVPR2 variants, 5 were truncating variants (3 frameshift and 2 nonsense) observed in 7 affected probands. Although each 7 probands with truncating variants were affected with NDI, the variants were also observed in unaffected females in 5 of the families (not uncommon for this condition).

Haploinsufficiency phenotype comments:

Loss of function variants in AVPR2 are the most common cause of nephrogenic diabetes insipidus (NDI), which is characterized by an inability to concentrate the urine resulting in polyuria and polydipsia. Manifestations of symptoms in untreated infants can lead to poor feeding, poor weight gain and irritability. AVPR2 is located on the X chromosome and therefore pathogenic variants in AVPR2 are associated with X-linked NDI. Typically males are more severely affected than carrier females, but depending on the level of X-inactivation skewing females with heterozygous AVPR2 variants can also manifest symptoms. Many additional studies exist supporting haploinsufficiency as the disease mechanism for AVPR2 associated NDI. A small number of missense variants have been shown to result in partial insensitivity leading to disease onset later in childhood (see GeneReviews for summary table of variants). In addition, gain of function mutations have been reported with nephrogenic syndrome of inappropriate antidiuresis.

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.

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

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.