rs759377924
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PM5PP3_ModeratePP5_Very_Strong
The NM_001126108.2(SLC12A3):c.1315G>A(p.Gly439Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000799 in 1,613,822 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G439V) has been classified as Likely pathogenic.
Frequency
Consequence
NM_001126108.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SLC12A3 | NM_001126108.2 | c.1315G>A | p.Gly439Ser | missense_variant | 10/26 | ENST00000563236.6 | |
SLC12A3 | NM_000339.3 | c.1315G>A | p.Gly439Ser | missense_variant | 10/26 | ||
SLC12A3 | NM_001126107.2 | c.1312G>A | p.Gly438Ser | missense_variant | 10/26 | ||
SLC12A3 | NM_001410896.1 | c.1312G>A | p.Gly438Ser | missense_variant | 10/26 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SLC12A3 | ENST00000563236.6 | c.1315G>A | p.Gly439Ser | missense_variant | 10/26 | 1 | NM_001126108.2 | A1 | |
SLC12A3 | ENST00000438926.6 | c.1315G>A | p.Gly439Ser | missense_variant | 10/26 | 1 | A1 | ||
SLC12A3 | ENST00000566786.5 | c.1312G>A | p.Gly438Ser | missense_variant | 10/26 | 1 | P4 | ||
SLC12A3 | ENST00000262502.5 | c.1312G>A | p.Gly438Ser | missense_variant | 10/26 | 5 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000788 AC: 12AN: 152206Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000163 AC: 41AN: 250818Hom.: 0 AF XY: 0.000133 AC XY: 18AN XY: 135742
GnomAD4 exome AF: 0.0000800 AC: 117AN: 1461616Hom.: 0 Cov.: 33 AF XY: 0.0000908 AC XY: 66AN XY: 727110
GnomAD4 genome ? AF: 0.0000788 AC: 12AN: 152206Hom.: 0 Cov.: 32 AF XY: 0.0000807 AC XY: 6AN XY: 74362
ClinVar
Submissions by phenotype
Familial hypokalemia-hypomagnesemia Pathogenic:9
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Oct 10, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 11, 2019 | Across a selection of the available literature, the SLC12A3 c.1315G>A (p.Gly439Ser) missense variant was found in a total of 15 individuals affected with Gitelman syndrome (GS). The p.Gly439Ser variant was found in a homozygous state in two individuals (one of whom was also homozygous for a second variant), in a compound heterozygous state in 12 individuals (including two siblings), and in a heterozygous state in one individual in whom a second variant was not identified (Mastroianni et al. 1996; Melander et al. 2000; UrbanovÅ et al. 2006; Tajima et al 2006; Favre et al. 2012; Berry et al. 2013; Brambilla et al. 2013; Bouchireb et al. 2014). The variant was found in a heterozygous state in one of 844 control chromosomes and is reported at a frequency of 0.0004 in the non-Finnish European population of the Exome Aggregation Consortium. De Jong et al. (2002) demonstrated that Xenopus oocytes expressing the p.Gly439Ser variant showed no significant sodium uptake and exhibited significant cellular mislocalization of the protein. Based on the collective evidence, the p.Gly439Ser variant is classified as pathogenic for Gitelman syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
Pathogenic, criteria provided, single submitter | clinical testing | European Hospital Georges Pompidou Genetics Department, Assistance Publique - Hôpitaux de Paris AP-HP | Apr 27, 2022 | ACMG criteria used:PM1 PM2 PM3 PP3 PP5 - |
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jul 15, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota | May 23, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jun 29, 2022 | - - |
Pathogenic, criteria provided, single submitter | research | Molecular Biology Laboratory, Fundació Puigvert | Feb 01, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 13, 2024 | Variant summary: SLC12A3 c.1315G>A (p.Gly439Ser) 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 0.00016 in 250818 control chromosomes (gnomAD). c.1315G>A has been reported in the literature in multiple individuals affected with Gitelman syndrome (examples: Mastrojanni_1996, Horak_2005, and Fava_2007). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 8900229, 17654016, 16343108). ClinVar contains an entry for this variant (Variation ID: 586601). Based on the evidence outlined above, the variant was classified as pathogenic. - |
not provided Pathogenic:5
Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Jun 22, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 11, 2023 | Published functional studies demonstrate a damaging effect due to an intracellular trafficking defect, with failure to reach the cell membrane (De Jong et al., 2002); 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: 17159356, 19451210, 19349556, 17654016, 24790334, 28700713, 28469853, 23475471, 12039972, 8900229, 25112827, 26830254, 23328711, 18391953, 15102966, 10988270, 31672324, 26121437, 22241817, 22009145, 31398183, 31589614, 33348466) - |
Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 24, 2023 | This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 439 of the SLC12A3 protein (p.Gly439Ser). This variant is present in population databases (rs759377924, gnomAD 0.03%). This missense change has been observed in individual(s) with Gitelman syndrome (PMID: 8900229, 17654016, 23475471, 25112827). 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: 586601). 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%. Experimental studies have shown that this missense change affects SLC12A3 function (PMID: 12039972). For these reasons, this variant has been classified as Pathogenic. - |
Familial aortopathy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 13, 2024 | Variant summary: MYLK c.1315G>A (p.Gly439Arg) results in a non-conservative amino acid change located in the Immunoglobulin subtype 2 domain (IPR003598) 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 2.8e-05 in 248090 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1315G>A in individuals affected with Aortopathy and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 21, 2022 | The c.1315G>A (p.G439S) alteration is located in exon 10 (coding exon 10) of the SLC12A3 gene. This alteration results from a G to A substitution at nucleotide position 1315, causing the glycine (G) at amino acid position 439 to be replaced by a serine (S). Based on data from gnomAD, the A allele has an overall frequency of 0.02% (44/282204) total alleles studied. The highest observed frequency was 0.03% (38/128698) of European (non-Finnish) alleles. This alteration has been detected in the homozygous state and as compound heterozygous in trans with other pathogenic SLC12A3 variants in multiple, unrelated individuals diagnosed with Gitelman syndrome (Mastroianni, 1996; Melander 2000; Urbanova, 2006; Tajima, 2006; Fava, 2007; Ji, 2008; Favre, 2012; Berry, 2013; Brambilla, 2013; Bouchireb, 2014; Bech, 2016; Zeng, 2019; Roser, 2020). This amino acid position is highly conserved in available vertebrate species. In vitro studies have shown that p.G439S results in the loss of function of the SLC12A3 protein (De Jong, 2002). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. - |
Bartter syndrome;C0268450:Familial hypokalemia-hypomagnesemia Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Sydney Genome Diagnostics, Children's Hospital Westmead | Aug 27, 2019 | This individual is heterozygous for the c.1315G>A variant in the SLC12A3 gene, which results in the amino acid substitution of glycine to serine at residue 439, p.(Gly439Ser). This variant has been reported in the gnomAD browser (http://gnomad.broadinstitute.org) with a very low allele frequency of 0.015% (42 out of 276,658 alleles).This variant has been previously described in multiple individuals with Gitelman syndrome, in either a homozygous or compound heterozygous state (Bouchireb et al 2014 BMC Pediatrics 14: 201; Vargas-Poussou et al 2011 J Am Soc Nephrol 22: 693-703). In addition, functional studies, using Xenopus oocytes harbouring the p.(Gly439Ser) variant, showed a loss of sodium ion uptake and exhibited significant cellular mis-localisation of the protein (De Jong et al 2002 J Am Soc Nephrol 13: 1442-1448). This variant is considered to be pathogenic according to the ACMG guidelines. (Evidence used: PS3, PM2, PM3_strong). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at