rs267607050
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PP3_ModeratePP5_Very_Strong
The NM_001126108.2(SLC12A3):c.488C>T(p.Thr163Met) variant causes a missense change. The variant allele was found at a frequency of 0.00000992 in 1,613,094 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 (★★). Synonymous variant affecting the same amino acid position (i.e. T163T) has been classified as Likely benign.
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.488C>T | p.Thr163Met | missense_variant | 3/26 | ENST00000563236.6 | |
SLC12A3 | NM_000339.3 | c.488C>T | p.Thr163Met | missense_variant | 3/26 | ||
SLC12A3 | NM_001126107.2 | c.485C>T | p.Thr162Met | missense_variant | 3/26 | ||
SLC12A3 | NM_001410896.1 | c.485C>T | p.Thr162Met | missense_variant | 3/26 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SLC12A3 | ENST00000563236.6 | c.488C>T | p.Thr163Met | missense_variant | 3/26 | 1 | NM_001126108.2 | A1 | |
SLC12A3 | ENST00000438926.6 | c.488C>T | p.Thr163Met | missense_variant | 3/26 | 1 | A1 | ||
SLC12A3 | ENST00000566786.5 | c.485C>T | p.Thr162Met | missense_variant | 3/26 | 1 | P4 | ||
SLC12A3 | ENST00000262502.5 | c.485C>T | p.Thr162Met | missense_variant | 3/26 | 5 | A1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152212Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000362 AC: 9AN: 248862Hom.: 0 AF XY: 0.0000223 AC XY: 3AN XY: 134580
GnomAD4 exome AF: 0.0000103 AC: 15AN: 1460882Hom.: 0 Cov.: 32 AF XY: 0.00000963 AC XY: 7AN XY: 726612
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152212Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74360
ClinVar
Submissions by phenotype
not provided Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 13, 2024 | Identified as a common variant with an allele frequency of 3.2% in a cohort of 310 Chinese patients diagnosed with Gitelman syndrome (Jiang et al., 2022); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 12112667, 30596175, 35591852, 34389731, 17472852, 25841442, 34604727, 36806220, 19033254, 22679066, 28469853, 21256383, 12686679, 31398183, 17000984, 36158002, 15687331, 34860177, 21051746, 26260218) - |
Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | May 14, 2021 | The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant appears to segregate with disease in at least one family, however, the available information does not rule out segregation due to chance. 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 | Oct 18, 2023 | This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 163 of the SLC12A3 protein (p.Thr163Met). This variant is present in population databases (rs267607050, gnomAD 0.04%). This missense change has been observed in individuals with Gitelman syndrome (PMID: 12112667, 21051746, 26260218, 30596175). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 242798). 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. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Jun 17, 2021 | - - |
Familial hypokalemia-hypomagnesemia Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jul 15, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Dec 24, 2021 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Jul 02, 2021 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at