ClinVar Miner

Submissions for variant NM_018979.4(WNK1):c.3859G>T (p.Ala1287Ser) (rs149186881)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000532745 SCV000649428 uncertain significance Hereditary sensory and autonomic neuropathy type IIA; Pseudohypoaldosteronism type 2C 2018-12-13 criteria provided, single submitter clinical testing This sequence change replaces alanine with serine at codon 1287 of the WNK1 protein (p.Ala1287Ser). The alanine residue is weakly conserved and there is a moderate physicochemical difference between alanine and serine. This variant is present in population databases (rs149186881, ExAC 0.02%) but has not been reported in the literature in individuals with a WNK1-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The serine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change that is not predicted to affect protein function, and is found in the population at an appreciable frequency. This variant is not anticipated to cause disease; however, the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Illumina Clinical Services Laboratory,Illumina RCV001113522 SCV001271301 benign Pseudohypoaldosteronism type 2C 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

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