Submissions for variant NM_001126108.2(SLC12A3):c.2186G>C (p.Gly729Ala)

Total submissions: 1

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004689526	SCV005185768	likely pathogenic	Familial hypokalemia-hypomagnesemia	2024-05-15	criteria provided, single submitter	clinical testing	Variant summary: SLC12A3 c.2186G>C (p.Gly729Ala) results in a non-conservative amino acid change located in the SLC12A transporter, C-terminal domain (IPR018491) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251092 control chromosomes (gnomAD). c.2186G>C has been reported in the literature in at least two compound heterozygous individuals affected with Gitelman syndrome (e.g., Vargas-Poussou_2011, Hureaux_2019). 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. The following publications have been ascertained in the context of this evaluation (PMID: 31672324, 21415153). No submitters have cited clinical-significance assessments for this variant to ClinVar. Additionally, a different missense variant affecting the same codon, c.2186G>T (p.Gly729Val), has been reported in the literature in multiple individuals affected with Gitelman syndrome (PMID: 11168953) and classified as pathogenic/likely pathogenic in ClinVar. Based on the evidence outlined above, the variant was classified as likely pathogenic.