Submissions for variant NM_001126108.2(SLC12A3):c.378del (p.Ser126fs)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003479792	SCV004223572	pathogenic	Familial hypokalemia-hypomagnesemia	2023-11-09	criteria provided, single submitter	clinical testing	Variant summary: SLC12A3 c.378delC (p.Ser126ArgfsX17) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Variants downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 249406 control chromosomes. c.378delC has been reported in the literature in at least one homozygous individual affected with Gitelman syndrome (e.g. Palazzo_2022). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003699117	SCV004467185	pathogenic	not provided	2023-10-17	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ser126Argfs*17) in the SLC12A3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SLC12A3 are known to be pathogenic (PMID: 20848653, 22009145, 25841442). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of SLC12A3-related conditions (PMID: 35628451). For these reasons, this variant has been classified as Pathogenic.