Submissions for variant NM_001126108.2(SLC12A3):c.1664C>T (p.Ser555Leu)

gnomAD frequency: 0.00008  dbSNP: rs148038173

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000796506	SCV000936024	pathogenic	not provided	2024-12-20	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 555 of the SLC12A3 protein (p.Ser555Leu). This variant is present in population databases (rs148038173, gnomAD 0.02%). This missense change has been observed in individuals with Gitelman syndrome (PMID: 11168953, 17329572, 21753071, 23328711). ClinVar contains an entry for this variant (Variation ID: 642947). 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%. Experimental studies have shown that this missense change affects SLC12A3 function (PMID: 17329572). For these reasons, this variant has been classified as Pathogenic.
Athena Diagnostics	RCV000796506	SCV001475519	pathogenic	not provided	2020-02-25	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population is consistent with pathogenicity. Found in at least one patient with expected phenotype for this gene. Predicted to have a damaging effect on the protein. In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. Assessment of experimental evidence suggests this variant results in abnormal protein function. Segregation with disease in affected and unaffected individualsfrom a single family.
GeneDx	RCV000796506	SCV001872701	pathogenic	not provided	2024-07-11	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect causing defective protein processing, location, and function (PMID: 17329572); 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: 21415153, 17059986, 17159356, 24790334, 11168953, 21753071, 27529443, 31672324, 33095447, 17329572, 23328711, 35611242, 36158002, 22009145, 26484179, 30596175)
Revvity Omics, Revvity	RCV001276376	SCV002022588	likely pathogenic	Familial hypokalemia-hypomagnesemia	2022-07-19	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001276376	SCV002055334	pathogenic	Familial hypokalemia-hypomagnesemia	2021-07-15	criteria provided, single submitter	clinical testing
DASA	RCV001276376	SCV002061211	pathogenic	Familial hypokalemia-hypomagnesemia	2022-01-05	criteria provided, single submitter	clinical testing	The c.1664C>T;p.(Ser555Leu) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 642947; PMID: 11168953; 17329572; 23328711; 21753071; 30596175; 22009145) - PS4. Well-established in vitro or in vivo functional studies support a damaging effect on the gene or gene product (PMID: 17329572) - PS3_supporting. The variant is present at low allele frequencies population databases (rs148038173– gnomAD 0.0007886%; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2_supporting. The p.(Ser555Leu) was detected in trans with a pathogenic variant (PMID: 30596175 ; 23328711; 22009145) - PM3_strong. In summary, the currently available evidence indicates that the variant is pathogenic.
European Hospital Georges Pompidou Genetics Department, Assistance Publique - Hôpitaux de Paris AP-HP	RCV001276376	SCV002513808	pathogenic	Familial hypokalemia-hypomagnesemia	2022-04-27	criteria provided, single submitter	clinical testing	ACMG criteria used:PS3, PS4, PM1, PM2, PP3, PP5
MGZ Medical Genetics Center	RCV001276376	SCV002580465	likely pathogenic	Familial hypokalemia-hypomagnesemia	2021-10-25	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV001276376	SCV002804749	pathogenic	Familial hypokalemia-hypomagnesemia	2024-02-27	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002537028	SCV003543517	pathogenic	Inborn genetic diseases	2022-10-25	criteria provided, single submitter	clinical testing	The c.1664C>T (p.S555L) alteration is located in exon 13 (coding exon 13) of the SLC12A3 gene. This alteration results from a C to T substitution at nucleotide position 1664, causing the serine (S) at amino acid position 555 to be replaced by a leucine (L). Based on data from gnomAD, the T allele has an overall frequency of 0.006% (17/282842) total alleles studied. The highest observed frequency was 0.012% (3/25094) of European (Finnish) alleles. This alteration has been reported in the homozygous state and in conjunction with other alterations in SLC12A3 in multiple individuals with Gitelman syndrome (Urbanová, 2006; Tajima, 2006; Godefroid, 2006; Riveira-Munoz, 2007; Vargas-Poussou, 2011; Balavoine, 2011; Glaudemans, 2012; Berry, 2013; Hureaux, 2019; Fujimura, 2019; Cruz, 2001; Oh, 2021). In addition, this alteration was shown to segregate with disease in a family with clinical features consistent with Gitelman syndrome (Godefroid, 2006). This amino acid position is highly conserved in available vertebrate species. Functional assays show reduced ion transport activity in Xenopus oocytes compared to controls (Riveira-Munoz, 2007). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
Genetics and Molecular Pathology, SA Pathology	RCV001276376	SCV004175507	pathogenic	Familial hypokalemia-hypomagnesemia	2022-12-19	criteria provided, single submitter	clinical testing	The SLC12A3 c.1664C>T variant is classified as Pathogenic (PS4_Moderate, PS3_supporting, PM1, PM3_Strong, PP3) The SLC12A3 c.1664C>T variant is a single nucleotide change in exon 13/26 of the SLC12A3 gene, which is predicted to change the amino acid serine at position 555 in the protein to leucine. The variant has been reported in many patients with Gitelman syndrome (PMID:30596175, 23328711, 11168953, 21753071, 17159356, 17059986, 33095447, 17329572). (PS4_Moderate). Functional studies have shown that the variant results in defective intrinsic activity (PMID:17329572) (PS3_supporting). This variant is located in the conserved amino acid permease domain (PM1). This variant has been detected in trans with a pathogenic variant for this recessive condition (PMID:17329572, 17059986) (PM3_strong). Computational predictions support a deleterious effect on the gene or gene product (PP3). The variant has been reported in dbSNP (rs148038173) and as disease causing in the HGMD database (CM014402). It has been reported as Pathogenic by other diagnostic laboratories (ClinVar Variation ID: 642947).
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV001276376	SCV005398916	pathogenic	Familial hypokalemia-hypomagnesemia	2024-10-09	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 serine to leucine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (17 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 classified as likely pathogenic or pathogenic by multiple clinical laboratories in ClinVar. This variant has also been observed in the literature in multiple compound heterozygous individuals with Gitelman syndrome (PMID: 17329572). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001276376	SCV005885984	pathogenic	Familial hypokalemia-hypomagnesemia	2025-02-18	criteria provided, single submitter	clinical testing	Variant summary: SLC12A3 c.1664C>T (p.Ser555Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of three in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6e-05 in 251448 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in SLC12A3 causing Familial Hypokalemia-Hypomagnesemia, allowing no conclusion about variant significance. c.1664C>T has been reported in the literature in individuals affected with Familial Hypokalemia-Hypomagnesemia (example: Riveira-Munoz_2007, Berry_2013). These data indicate that the variant is likely to be associated with disease. Experimental studies have shown that this missense changes the normal function of the protein (Riveira-Munoz_2007). The following publications have been ascertained in the context of this evaluation (PMID: 17329572, 23328711). ClinVar contains an entry for this variant (Variation ID: 642947). Based on the evidence outlined above, the variant was classified as pathogenic.
Natera, Inc.	RCV001276376	SCV001462611	pathogenic	Familial hypokalemia-hypomagnesemia	2020-09-16	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004745590	SCV005354381	pathogenic	SLC12A3-related disorder	2024-09-27	no assertion criteria provided	clinical testing	The SLC12A3 c.1664C>T variant is predicted to result in the amino acid substitution p.Ser555Leu. This variant has been reported in many unrelated individuals to be pathogenic for Gitelman syndrome due to impaired ion transport activity (Riveira-Munoz et al. 2007. PubMed ID: 17329572; Berry et al. 2013. PubMed ID: 23328711; Fujimura et al 2019. PubMed ID: 30596175). This variant is reported in 0.012% of alleles in individuals of European (Finnish) descent in gnomAD and has been interpreted as likely pathogenic or pathogenic by multiple laboratories in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/642947/). Based on the available evidence, we classify this variant as pathogenic.