ClinGen Dosage Sensitivity Curation Page

AVPR2

Curation Status: Complete

Gene Information

Location Information

Evidence for Loss Phenotypes

Evidence for loss of function 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).

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.

Evidence for Triplosenstive Phenotype

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.

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.