ClinVar Miner

Submissions for variant NM_000486.5(AQP2):c.140C>T (p.Ala47Val) (rs995684800)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000778365 SCV000914582 uncertain significance Nephrogenic diabetes insipidus, autosomal 2018-08-09 criteria provided, single submitter clinical testing The AQP2 c.140C>T (p.Ala47Val) variant is a missense variant that has been reported in a homozygous state in two siblings with nephrogenic diabetes insipidus who were born to a consanguineous family (Marr et al. 2002; Müller et al. 2002). Control data are unavailable for the p.Ala47Val variant, which is reported at a frequency of 0.000058 in the East Asian population of the Genome Aggregation Database. This frequency is based on one allele only in a region of good sequencing coverage. Therefore, the variant is presumed to be rare. Functional studies conducted in Xenopus oocytes have shown that the variant results in reduced water permeability, reduced single channel permeability, impaired membrane trafficking, and altered glycosylation compared to wildtype (Marr et al. 2002), and it has been reported to result in misfolding and to be retained in the ER (Yang et al. 2009). Ala47Val AQP2 also did not recover function when expressed in Xenopus oocytes in conjunction with wildtype AQP2 (El Tarazi et al. 2016). Based on the limited evidence available, the p.Ala47Val variant is classified as a variant of unknown significance but suspicious for pathogenicity for nephrogenic diabetes insipidus. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

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