Submissions for variant NM_001126108.2(SLC12A3):c.815T>C (p.Leu272Pro)

gnomAD frequency: 0.00003  dbSNP: rs568513106

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Gharavi Laboratory, Columbia University	RCV000681951	SCV000809439	likely pathogenic	not provided	2018-09-16	criteria provided, single submitter	research
Fulgent Genetics, Fulgent Genetics	RCV000191129	SCV002790527	likely pathogenic	Familial hypokalemia-hypomagnesemia	2021-12-24	criteria provided, single submitter	clinical testing
Invitae	RCV000681951	SCV003441841	likely pathogenic	not provided	2023-12-14	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 272 of the SLC12A3 protein (p.Leu272Pro). This variant is present in population databases (rs568513106, gnomAD 0.004%). This missense change has been observed in individuals with Gitelman syndrome (PMID: 18391953, 31398183). ClinVar contains an entry for this variant (Variation ID: 209191). 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 expected to disrupt SLC12A3 protein function with a positive predictive value of 95%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000191129	SCV004241719	pathogenic	Familial hypokalemia-hypomagnesemia	2023-12-04	criteria provided, single submitter	clinical testing	Variant summary: SLC12A3 c.815T>C (p.Leu272Pro) results in a non-conservative amino acid change located in the Amino acid permease/ SLC12A domain (IPR004841) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251392 control chromosomes (gnomAD). c.815T>C has been reported in the literature in multiple compound heterozygous individuals affected with Gitelman syndrome (Ji_2008, Glaudemans_2011, Peng_2017, Zhang_2023). These data indicate that the variant is very likely to 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: 22009145, 18391953, 28700713, 21415153, 36806220). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV000191129	SCV000245537	pathogenic	Familial hypokalemia-hypomagnesemia		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000681951	SCV001926542	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000681951	SCV001956135	pathogenic	not provided		no assertion criteria provided	clinical testing