Submissions for variant NM_032387.5(WNK4):c.3553C>T (p.Arg1185Cys)

gnomAD frequency: 0.00024  dbSNP: rs137853095

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000731744	SCV000859593	uncertain significance	not provided	2018-02-06	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000008102	SCV001286787	uncertain significance	Pseudohypoaldosteronism type 2B	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
GeneDx	RCV000731744	SCV002559497	uncertain significance	not provided	2022-01-27	criteria provided, single submitter	clinical testing	Observed in three family members with Pseudohypoaldosteronism type II from the published literature (Wilson et al., 2001); Published functional studies demonstrate a damaging effect with reduced baseline inhibition of WNK4 activity and reduced surface expression of sodium chloride cotransporter (NCC) consistent with a gain of function (Cai et al., 2006; Na et al., 2013); 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: 16688122, 34927382, 23054253, 11498583, 22114204)
Fulgent Genetics, Fulgent Genetics	RCV000008102	SCV002797065	likely benign	Pseudohypoaldosteronism type 2B	2024-02-14	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000731744	SCV005838709	uncertain significance	not provided	2024-05-02	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1185 of the WNK4 protein (p.Arg1185Cys). This variant is present in population databases (rs137853095, gnomAD 0.03%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with Gordon's syndrome (PMID: 11498583). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 7663). 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 WNK4 protein function with a negative predictive value of 95%. Experimental studies have shown that this missense change affects WNK4 function (PMID: 16688122, 23054253). 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.
OMIM	RCV000008102	SCV000028307	pathogenic	Pseudohypoaldosteronism type 2B	2001-08-10	no assertion criteria provided	literature only
GeneReviews	RCV000008102	SCV000503031	not provided	Pseudohypoaldosteronism type 2B		no assertion provided	literature only