ClinVar Miner

Submissions for variant NM_213655.4(WNK1):c.2152C>T (p.Arg718Cys) (rs786205473)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Developmental Genetics Unit,King Faisal Specialist Hospital & Research Centre RCV000171203 SCV000221400 likely pathogenic not provided no assertion criteria provided research
Invitae RCV000705508 SCV000834508 uncertain significance Hereditary sensory and autonomic neuropathy type IIA; Pseudohypoaldosteronism type 2C 2018-10-18 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 718 of the WNK1 protein (p.Arg718Cys). The arginine residue is weakly conserved and there is a large physicochemical difference between arginine and cysteine. The WNK1 gene has multiple clinically relevant transcripts. The p.Arg718Cys variant occurs in alternate transcript NM_213655.4, which corresponds to position c.2139+2852C>T in NM_018979.3, the primary transcript listed in the Methods. While this variant is not present in population databases, the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been reported as homozygous in an individual affected with global proximal weakness, bilateral mild calf hypertrophy and marked lordotic gait (PMID: 27671536). ClinVar contains an entry for this variant (Variation ID: 191028). Algorithms developed to predict the effect of missense changes on protein structure and function (PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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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