ClinVar Miner

Submissions for variant NM_018979.4(WNK1):c.3209G>C (p.Ser1070Thr) (rs760251215)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000548773 SCV000649415 uncertain significance Hereditary sensory and autonomic neuropathy type IIA; Pseudohypoaldosteronism type 2C 2017-05-23 criteria provided, single submitter clinical testing This sequence change replaces serine with threonine at codon 1070 of the WNK1 protein (p.Ser1070Thr). The serine residue is highly conserved and there is a small physicochemical difference between serine and threonine. This variant also falls at the last nucleotide of exon 13 of the WNK1 coding sequence, which is part of the consensus splice site for this exon. This variant is present in population databases (rs760251215, ExAC 0.01%) 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 (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. Nucleotide substitutions within the consensus splice site are relatively common causes of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of nucleotide changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. In summary, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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