Submissions for variant NM_018979.4(WNK1):c.5258A>G (p.Lys1753Arg)

gnomAD frequency: 0.00001  dbSNP: rs752078094

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000383349	SCV000381988	likely benign	Pseudohypoaldosteronism type 2C	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Invitae	RCV000687160	SCV000814712	uncertain significance	Neuropathy, hereditary sensory and autonomic, type 2A; Pseudohypoaldosteronism type 2C	2023-12-20	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 2005 of the WNK1 protein (p.Lys2005Arg). This variant is present in population databases (rs752078094, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with WNK1-related conditions. ClinVar contains an entry for this variant (Variation ID: 310833). 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%. 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.
GeneDx	RCV001770248	SCV002003954	uncertain significance	not provided	2021-04-26	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Ambry Genetics	RCV002356421	SCV002655144	uncertain significance	Inborn genetic diseases	2020-09-09	criteria provided, single submitter	clinical testing	The p.K2005R variant (also known as c.6014A>G), located in coding exon 19 of the WNK1 gene, results from an A to G substitution at nucleotide position 6014. The lysine at codon 2005 is replaced by arginine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.