ClinVar Genomic variation as it relates to human health

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].

Experimental studies have shown that this missense change affects AQP2 function (PMID: 12191971, 20711567). For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on AQP2 protein function. ClinVar contains an entry for this variant (Variation ID: 446860). This missense change has been observed in individuals with autosomal recessive diabetes insipidus (PMID: 12191971, 19147915, 26069764). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs149659001, gnomAD 0.003%). This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 71 of the AQP2 protein (p.Val71Met).

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with diabetes insipidus, nephrogenic, 2 (MIM#125800). Missense variants have been described with either a dominant negative or loss of function mechanism. Protein truncating variants have a loss of function mechanism, whereas frameshift variants causing an elongation are dominant negative (OMIM, PMID: 12191971, PMID: 26069764, PMID: 11536078). (I) 0108 - This gene is associated with both recessive and dominant disease. Loss of function variants result in recessive disease, whereas dominant negative variants result in dominant disease (PMID: 12191971, PMID: 26069764, PMID: 11536078). (I) 0200 - Variant is predicted to result in a missense amino acid change from valine to methionine. (I) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 (4 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v3) (1 heterozygote, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated CII domain (PMID: 26069764). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported several times as pathogenic, and observed in multiple homozygous individuals with diabetes insipidus (ClinVar, PMID: 12191971, PMID: 30976394, PMID: 26069764). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Expression of this variant in oocytes showed significantly reduced water permeability and protein mislocalization (PMID: 12191971). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

The missense c.211G>A (p.Val71Met) variant in the AQP2 gene which is located in a mutational hot spot has been reported previously in a homozygous state in individuals affected with nephrogenic diabetes insipidus (NDI) (Bichet et al., 2016). Experimental studies have shown that this missense change affects the AQP2 function (Marr et al., 2002; Lussier et al., 2010). The amino acid Val at position 71 is changed to a Met changing protein sequence and it might alter its composition and physico-chemical properties. This variant has been reported to the ClinVar database as Pathogenic. Multiple lines of computational evidence (Polyphen - Damaging, SIFT - Damaging and MutationTaster - Disease causing) predict a damaging effect on protein structure and function for this variant. The amino acid change p.Val71Met in AQP2 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.