Submissions for variant NM_001126108.2(SLC12A3):c.1145C>T (p.Thr382Met)

gnomAD frequency: 0.00006  dbSNP: rs187885782

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001223584	SCV001395740	pathogenic	not provided	2025-01-12	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 382 of the SLC12A3 protein (p.Thr382Met). This variant is present in population databases (rs187885782, gnomAD 0.02%). This missense change has been observed in individual(s) with Gitelman syndrome (PMID: 18391953, 21753071, 23328711, 25838649, 26825084). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 951623). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt SLC12A3 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV001536124	SCV001752841	likely pathogenic	Familial hypokalemia-hypomagnesemia	2021-06-30	criteria provided, single submitter	clinical testing
GeneDx	RCV001223584	SCV002520284	likely pathogenic	not provided	2021-11-18	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: 27529443, 18391953, 17699451, 25838649, 31398183, 26825084, 21753071, 23328711)
MGZ Medical Genetics Center	RCV001536124	SCV002580241	uncertain significance	Familial hypokalemia-hypomagnesemia	2021-10-26	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV001536124	SCV005087174	pathogenic	Familial hypokalemia-hypomagnesemia	2023-07-17	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Gitelman syndrome (MIM#263800). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from threonine to methionine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 15 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated amino acid permease domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in more than ten unrelated individuals with Gitelman syndrome (ClinVar, PMID: 26825084, 21753071, 25838649, 23328711, 31398183, 18391953). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Natera, Inc.	RCV001536124	SCV002089345	likely pathogenic	Familial hypokalemia-hypomagnesemia	2020-01-23	no assertion criteria provided	clinical testing