rs775931992
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2PM5PP3_StrongPP5_Very_Strong
The NM_001126108.2(SLC12A3):c.1195C>T(p.Arg399Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000199 in 1,611,390 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. R399H) has been classified as Likely pathogenic.
Frequency
Consequence
NM_001126108.2 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SLC12A3 | NM_001126108.2 | c.1195C>T | p.Arg399Cys | missense_variant | 10/26 | ENST00000563236.6 | |
SLC12A3 | NM_000339.3 | c.1195C>T | p.Arg399Cys | missense_variant | 10/26 | ||
SLC12A3 | NM_001126107.2 | c.1192C>T | p.Arg398Cys | missense_variant | 10/26 | ||
SLC12A3 | NM_001410896.1 | c.1192C>T | p.Arg398Cys | missense_variant | 10/26 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SLC12A3 | ENST00000563236.6 | c.1195C>T | p.Arg399Cys | missense_variant | 10/26 | 1 | NM_001126108.2 | A1 | |
SLC12A3 | ENST00000438926.6 | c.1195C>T | p.Arg399Cys | missense_variant | 10/26 | 1 | A1 | ||
SLC12A3 | ENST00000566786.5 | c.1192C>T | p.Arg398Cys | missense_variant | 10/26 | 1 | P4 | ||
SLC12A3 | ENST00000262502.5 | c.1192C>T | p.Arg398Cys | missense_variant | 10/26 | 5 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152176Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000121 AC: 3AN: 247056Hom.: 0 AF XY: 0.00000748 AC XY: 1AN XY: 133690
GnomAD4 exome AF: 0.0000192 AC: 28AN: 1459214Hom.: 0 Cov.: 33 AF XY: 0.0000207 AC XY: 15AN XY: 725740
GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152176Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74338
ClinVar
Submissions by phenotype
Familial hypokalemia-hypomagnesemia Pathogenic:6
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Oct 22, 2021 | - - |
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:PS1 PS4 PM1 PM2 PP3 PP4 PP5 - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Dec 22, 2021 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jul 15, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | The missense variant c.1195C>T, p.Arg399Cy in the SLC12A3 gene has previously been reported in homozygous and compound heterozygous state in individuals affected with Gitelman syndrome (Cruz DN et al., Kaito H et al.). This variant disrupts the p.Arg399 amino acid residue in SLC12A3. Other variant(s) that disrupt this residue have been observed in individuals with SLC12A3-related conditions (Berry MR et. al., Kaito H et al). The p.Arg399Cys variant is novel (not in any individuals) in 1000 Genomes and has frequency of 0.0012% in gnomAD database. This variant has been reported to the ClinVar database as Pathogenic. The variant is predicted to be damaging by both SIFT and PolyPhen2. The residue is conserved across species. The amino acid change p.Arg399Cys in SLC12A3 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The p.Arg399Cys variant is novel (not in any individuals) in 1000 Genomes. For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Apr 10, 2015 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 14, 2023 | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 399 of the SLC12A3 protein (p.Arg399Cys). This variant is present in population databases (rs775931992, gnomAD 0.003%). This missense change has been observed in individuals with Gitleman syndrome (PMID: 11168953, 17414160, 18391953, 25165177, 26121437). ClinVar contains an entry for this variant (Variation ID: 448391). 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%. This variant disrupts the p.Arg399 amino acid residue in SLC12A3. Other variant(s) that disrupt this residue have been observed in individuals with SLC12A3-related conditions (PMID: 18391953, 23328711, 28469853), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at