Submissions for variant NM_018979.4(WNK1):c.1905T>A (p.Asp635Glu)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV003231657	SCV003929595	likely pathogenic	not provided	2022-12-01	criteria provided, single submitter	clinical testing	Published functional studies in a mouse model demonstrate a damaging effect (Louis-Dit-Picard er al., 2020); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32790646)
Labcorp Genetics (formerly Invitae), Labcorp	RCV005216025	SCV005852181	likely pathogenic	Neuropathy, hereditary sensory and autonomic, type 2A; Pseudohypoaldosteronism type 2C	2024-08-05	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 635 of the WNK1 protein (p.Asp635Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant pseudohypoaldosteronism type 2C (PHA2C) (PMID: 32790646; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 2504197). 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 with a negative predictive value of 95%. Experimental studies have shown that this missense change affects WNK1 function (PMID: 32790646). This variant disrupts the p.Asp635 amino acid residue in WNK1. Other variant(s) that disrupt this residue have been observed in individuals with WNK1-related conditions (PMID: 34159796), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.