ClinVar Miner

Submissions for variant NM_018979.4(WNK1):c.5462C>T (p.Ala1821Val)

gnomAD frequency: 0.00004  dbSNP: rs371264719
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000506465 SCV000605616 uncertain significance not specified 2016-09-28 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV001508684 SCV001715004 uncertain significance not provided 2019-04-27 criteria provided, single submitter clinical testing
Johns Hopkins Genomics, Johns Hopkins University RCV002282191 SCV002570399 uncertain significance Pseudohypoaldosteronism type 2C 2022-07-06 criteria provided, single submitter clinical testing This WNK1 missense variant (rs371264719 ) is rare (<0.1%) in a large population dataset (gnomAD v3.1.2: 5/152130 total alleles; 0.0033%; no homozygotes). It has been reported in ClinVar (Variation ID 440421), but has not been reported in the literature, to our knowledge. Three bioinformatic tools queried predict that this substitution would be tolerated, and the alanine residue at this position is evolutionarily conserved across very few species assessed with most species having valine at this position. We consider the clinical significance of c.5462C>T to be uncertain at this time.
Invitae RCV002527373 SCV003477950 uncertain significance Neuropathy, hereditary sensory and autonomic, type 2A; Pseudohypoaldosteronism type 2C 2022-03-14 criteria provided, single submitter clinical testing 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt WNK1 protein function. ClinVar contains an entry for this variant (Variation ID: 440421). This variant has not been reported in the literature in individuals affected with WNK1-related conditions. This variant is present in population databases (rs371264719, gnomAD 0.02%). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 2073 of the WNK1 protein (p.Ala2073Val).

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