chr16-56884142-C-T
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PM5PP3_ModeratePP5_Very_Strong
The NM_001126108.2(SLC12A3):c.1763C>T(p.Ala588Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000248 in 1,614,074 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. A588E) 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 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SLC12A3 | NM_001126108.2 | c.1763C>T | p.Ala588Val | missense_variant | 14/26 | ENST00000563236.6 | |
SLC12A3 | NM_000339.3 | c.1763C>T | p.Ala588Val | missense_variant | 14/26 | ||
SLC12A3 | NM_001126107.2 | c.1760C>T | p.Ala587Val | missense_variant | 14/26 | ||
SLC12A3 | NM_001410896.1 | c.1760C>T | p.Ala587Val | missense_variant | 14/26 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SLC12A3 | ENST00000563236.6 | c.1763C>T | p.Ala588Val | missense_variant | 14/26 | 1 | NM_001126108.2 | A1 | |
SLC12A3 | ENST00000438926.6 | c.1763C>T | p.Ala588Val | missense_variant | 14/26 | 1 | A1 | ||
SLC12A3 | ENST00000566786.5 | c.1760C>T | p.Ala587Val | missense_variant | 14/26 | 1 | P4 | ||
SLC12A3 | ENST00000262502.5 | c.1760C>T | p.Ala587Val | missense_variant | 14/26 | 5 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152228Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000239 AC: 6AN: 251084Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135738
GnomAD4 exome AF: 0.0000246 AC: 36AN: 1461846Hom.: 0 Cov.: 34 AF XY: 0.0000316 AC XY: 23AN XY: 727226
GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152228Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4AN XY: 74364
ClinVar
Submissions by phenotype
Familial hypokalemia-hypomagnesemia Pathogenic:3
Likely pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 1996 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | DASA | Jan 05, 2022 | The c.1763C>T;p.(Ala588Val) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 8591; OMIM: 600968.0008; PMID: 17329572; 23328711) - 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 (rs121909382– gnomAD 0.0002628%; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2_supporting. The p.(Ala588Val) was detected in trans with a pathogenic variant (PMID: 23328711) - PM3. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic. - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 08, 2024 | This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 588 of the SLC12A3 protein (p.Ala588Val). This variant is present in population databases (rs121909382, gnomAD 0.02%). This missense change has been observed in individuals with Gitelman syndrome (PMID: 17329572, 23328711). ClinVar contains an entry for this variant (Variation ID: 8591). 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: 17329572). This variant disrupts the p.Ala588 amino acid residue in SLC12A3. Other variant(s) that disrupt this residue have been observed in individuals with SLC12A3-related conditions (PMID: 23328711), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Feb 16, 2022 | Published functional studies demonstrate the same level of activity as non-injected oocytes, a positive intracellular and plasma membrane staining, and complex glycosylation and presence in both cell surface and cytoplasm contrasting with a lack of intrinsic activity (Riveira-Munoz et al., 2007); 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: 30305584, 27872838, 17329572, 8528245, 31589614, 33348466, 33775700, 23328711) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at