Submissions for variant NM_018979.4(WNK1):c.3578G>A (p.Ser1193Asn)

gnomAD frequency: 0.00045  dbSNP: rs72650720

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000175092	SCV000226521	uncertain significance	not provided	2016-09-07	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000313205	SCV000381955	benign	Pseudohypoaldosteronism type 2C	2018-01-13	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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Invitae	RCV001081613	SCV000649422	likely benign	Neuropathy, hereditary sensory and autonomic, type 2A; Pseudohypoaldosteronism type 2C	2024-01-25	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000999891	SCV000884930	uncertain significance	not specified	2019-02-11	criteria provided, single submitter	clinical testing	The WNK1 c.3578G>A; p.Ser1193Asn variant (rs72650720, ClinVar variant ID 194667), to our knowledge, is not reported in the medical literature or gene specific variation databases. This variant is listed in the genome Aggregation Database (gnomAD) with an overall population frequency of 0.05% (identified on 155 out of 282,826 chromosomes, including one homozygote). The serine at position 1193 is highly conserved, considering 18 species, and computational analyses of the effects of the p.Ser1193Asn variant on protein structure and function make conflicting predictions (SIFT: damaging, PolyPhen-2: benign). Based on the available information, the clinical significance of the p.Ser1193Asn variant cannot be determined with certainty.
Mayo Clinic Laboratories, Mayo Clinic	RCV000175092	SCV002541178	uncertain significance	not provided	2022-08-04	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002326955	SCV002633124	uncertain significance	Inborn genetic diseases	2022-03-28	criteria provided, single submitter	clinical testing	The p.S1445N variant (also known as c.4334G>A), located in coding exon 16 of the WNK1 gene, results from a G to A substitution at nucleotide position 4334. The serine at codon 1445 is replaced by asparagine, 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.
PreventionGenetics, part of Exact Sciences	RCV003955035	SCV004767003	likely benign	WNK1-related condition	2023-09-13	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).