rs202114767
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 12P and 1B. PM2PM5PP5_Very_StrongBP4
The NM_001126108.2(SLC12A3):c.2864G>A(p.Arg955Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000119 in 1,613,828 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R955W) 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 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SLC12A3 | NM_001126108.2 | c.2864G>A | p.Arg955Gln | missense_variant | 25/26 | ENST00000563236.6 | |
MIR6863 | NR_106923.1 | downstream_gene_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SLC12A3 | ENST00000563236.6 | c.2864G>A | p.Arg955Gln | missense_variant | 25/26 | 1 | NM_001126108.2 | A1 | |
MIR6863 | ENST00000636112.1 | downstream_gene_variant |
Frequencies
GnomAD3 genomes ? AF: 0.0000788 AC: 12AN: 152216Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000151 AC: 38AN: 251492Hom.: 0 AF XY: 0.000125 AC XY: 17AN XY: 135922
GnomAD4 exome AF: 0.000123 AC: 180AN: 1461612Hom.: 0 Cov.: 31 AF XY: 0.000117 AC XY: 85AN XY: 727120
GnomAD4 genome ? AF: 0.0000788 AC: 12AN: 152216Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3AN XY: 74368
ClinVar
Submissions by phenotype
not provided Pathogenic:5
Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Dec 15, 2020 | The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). Assessment of experimental evidence suggests this variant results in abnormal protein function. Study showed this variant to significantly reduce sodium uptake compared to wild-type (PMID: 12039972). 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 964 of the SLC12A3 protein (p.Arg964Gln). This variant is present in population databases (rs202114767, gnomAD 0.2%). This missense change has been observed in individuals with Gitelman syndrome (PMID: 8528245, 17654016, 21415153, 22214629, 30596175). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Arg955Gln. ClinVar contains an entry for this variant (Variation ID: 417864). 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. - |
Likely pathogenic, no assertion criteria provided | research | Gharavi Laboratory, Columbia University | Sep 16, 2018 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 31, 2023 | 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: 12039972, 8528245, 21415153, 15206555, 18391953, 31589614, 22214629, 35327948, 17654016, 19508680, 30596175, 33348466, 35785516, Yanan2023[noPMID], 22009145) - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Aug 01, 2023 | SLC12A3: PM3:Very Strong, PM2, PM5, PS3:Supporting, BP4 - |
Familial hypokalemia-hypomagnesemia Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | May 19, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | May 10, 2022 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jul 15, 2021 | - - |
Pathogenic, no assertion criteria provided | research | Division of Human Genetics, Children's Hospital of Philadelphia | Sep 23, 2015 | - - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 05, 2020 | The c.2891G>A (p.R964Q) alteration is located in exon 25 (coding exon 25) of the SLC12A3 gene. This alteration results from a G to A substitution at nucleotide position 2891, causing the arginine (R) at amino acid position 964 to be replaced by a glutamine (Q). Based on data from the Genome Aggregation Database (gnomAD) database, the SLC12A3 c.2891G>A alteration was observed in 0.01% (41/282888) of total alleles studied, with a frequency of 0.17% (18/10370) in the Ashkenazi Jewish subpopulation. This alteration has been reported in multiple patients with Gitelman syndrome in both the homozygous and compound heterozygous states (Enya, 2004; Fava, 2007; Nakamura, 2010; Vargas-Poussou, 2011; Glaudemans, 2012; Ito, 2012; Fujimura, 2019). This amino acid position is well conserved in available vertebrate species. The in silico prediction for the p.R964Q alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at