Submissions for variant NM_018979.4(WNK1):c.3188C>T (p.Thr1063Ile)

gnomAD frequency: 0.00013  dbSNP: rs201379287

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000383285	SCV000381942	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000647831	SCV000769634	likely benign	Neuropathy, hereditary sensory and autonomic, type 2A; Pseudohypoaldosteronism type 2C	2023-12-22	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002374531	SCV002626070	likely benign	Inborn genetic diseases	2024-01-24	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003323505	SCV004029592	uncertain significance	not specified	2023-07-26	criteria provided, single submitter	clinical testing	Variant summary: WNK1 c.3188C>T (p.Thr1063Ile) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00017 in 251472 control chromosomes, predominantly at a frequency of 0.00035 within the Non-Finnish European subpopulation in the gnomAD database (i.e. in 44 carriers). The high number of carriers in controls suggest that the variant is likely not associated with a dominant, early onset, high penetrance disease phenotype. On th other hand, the variant, c.3188C>T, has been reported in the literature in a homozygous individual, who underwent whole genome sequencing (WGS) however, no phenotype info was provided (Stranneheim_2021). This report does not provide unequivocal conclusions about association of the variant with Neuropathy, Hereditary Sensory and Autonomic, Type 2A. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 33726816). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance.
GeneDx	RCV001535659	SCV005326150	uncertain significance	not provided	2023-07-27	criteria provided, single submitter	clinical testing	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: 33726816)
GenomeConnect - Invitae Patient Insights Network	RCV001535659	SCV001749713	not provided	not provided		no assertion provided	phenotyping only	Variant interpreted as Likely benign and reported on 01-28-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.