ClinVar Miner

Submissions for variant NM_018979.4(WNK1):c.2140-2423G>A (rs201042606)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000519535 SCV000621675 uncertain significance not provided 2017-10-17 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the WNK1 gene. The G1124E variant hasnot been published as a pathogenic variant, nor has it been reported as a benign variant to ourknowledge. The G1124E variant is observed in 40/126,596 (0.03%) alleles from individuals ofEuropean background (Lek et al., 2016). The G1124E variant is a non-conservative amino acidsubstitution, which is likely to impact secondary protein structure as these residues differ in polarity,charge, size and/or other properties. This substitution occurs at a position that is not conserved. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to theprotein structure/function. Therefore, based on the currently available information, it is unclearwhether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000819734 SCV000960411 uncertain significance Hereditary sensory and autonomic neuropathy type IIA; Pseudohypoaldosteronism type 2C 2018-12-26 criteria provided, single submitter clinical testing This sequence change replaces glycine with glutamic acid at codon 1124 of the WNK1 protein (p.Gly1124Glu). The glycine residue is weakly conserved and there is a moderate physicochemical difference between glycine and glutamic acid. This variant is present in population databases (rs201042606, ExAC 0.03%). This variant has not been reported in the literature in individuals with WNK1-related conditions. ClinVar contains an entry for this variant (Variation ID: 452834). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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