ClinVar Genomic variation as it relates to human health

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Loss of function and gain of function are known mechanisms of disease in this gene and are associated with nephrogenic diabetes insipidus (MIM#304800) and nephrogenic syndrome of inappropriate antidiuresis (MIM#300539), respectively (PMID: 27355191). (I) 0109 - This gene is known to be associated with X-linked recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to cysteine. (I) 0253 - Variant is hemizygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 1 heterozygote, 0 homozygotes, 0 hemizygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2: 1 heterozygote, 0 homozygotes, 0 hemizygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (I) 0600 - Variant is located in the annotated transmembrane domain 3 (PMID: 15872203, 29546600). (I) 0702 - Comparable variants have strong previous evidence for pathogenicity. p.(Arg137Leu) has been shown to cause nephrogenic syndrome of inappropriate antidiuresis (ClinVar; PMID: 15872203, 29546600). p.(Arg137His) and p.(Arg137Gly) have been shown to cause nephrogenic diabetes insipidus (ClinVar; PMID: 8104196, 15872203, 27117808). (SP) 0801 - Strong previous evidence of pathogenicity in unrelated individuals. This variant has been previously reported as pathogenic in patients with nephrogenic syndrome of inappropriate antidiuresis (ClinVar, PMID: 15872203, 17229917, 29546600) (SP) 1002 - Moderate functional evidence supporting abnormal protein function. Functional studies showed that this variant caused constitutive activation of the receptor with high levels of cAMP (PMID: 15872203). (SP) 1205 - This variant has been shown to be maternally inherited. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

Same or different nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000010854, PMID:15872203). The variant has been reported to co-segregate with the disease in at least 3 similarly affected relatives/individuals in the same family or similarly affected unrelated families (PMID: 20159941). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 20159941). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000035739, PMID:27117808,8104196,15872203). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.93>=0.6, 3CNET: 0.921>=0.75). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.0000057). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

Published functional studies demonstrate that R137C results in constitutive activation of the AVP receptor with a 4-fold increase in basal cAMP production (Feldman et al., 2005; Tiulpakov et al., 2016; Ranieri et al., 2019); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20159941, 16843086, 20631022, 19542240, 34645113, 21834801, 27355191, 17229917, 15872203, 18622631, 18753429, 32499611, 31486901, 26715131, 22154540, 29472987, 32486031)