rs371443644
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong
The NM_001126108.2(SLC12A3):โc.179C>Tโ(p.Thr60Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000316 in 1,614,094 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 (โ โ ). Synonymous variant affecting the same amino acid position (i.e. T60T) 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 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SLC12A3 | NM_001126108.2 | c.179C>T | p.Thr60Met | missense_variant | 1/26 | ENST00000563236.6 | |
SLC12A3 | NM_000339.3 | c.179C>T | p.Thr60Met | missense_variant | 1/26 | ||
SLC12A3 | NM_001126107.2 | c.179C>T | p.Thr60Met | missense_variant | 1/26 | ||
SLC12A3 | NM_001410896.1 | c.179C>T | p.Thr60Met | missense_variant | 1/26 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SLC12A3 | ENST00000563236.6 | c.179C>T | p.Thr60Met | missense_variant | 1/26 | 1 | NM_001126108.2 | A1 | |
SLC12A3 | ENST00000438926.6 | c.179C>T | p.Thr60Met | missense_variant | 1/26 | 1 | A1 | ||
SLC12A3 | ENST00000566786.5 | c.179C>T | p.Thr60Met | missense_variant | 1/26 | 1 | P4 | ||
SLC12A3 | ENST00000262502.5 | c.179C>T | p.Thr60Met | missense_variant | 1/26 | 5 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000328 AC: 5AN: 152228Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000557 AC: 14AN: 251452Hom.: 0 AF XY: 0.0000662 AC XY: 9AN XY: 135912
GnomAD4 exome AF: 0.0000315 AC: 46AN: 1461866Hom.: 0 Cov.: 32 AF XY: 0.0000316 AC XY: 23AN XY: 727242
GnomAD4 genome ? AF: 0.0000328 AC: 5AN: 152228Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3AN XY: 74376
ClinVar
Submissions by phenotype
Familial hypokalemia-hypomagnesemia Pathogenic:10
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | European Hospital Georges Pompidou Genetics Department, Assistance Publique - Hรดpitaux de Paris AP-HP | Apr 27, 2022 | ACMG criteria used:PS3, PS4, PM2, PP3, PP5 - |
Pathogenic, no assertion criteria provided | clinical testing | Department of Pediatrics, Taizhou Central Hospital, Taizhou University Hospital | Feb 01, 2024 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 01, 2013 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jul 15, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | 3billion | Oct 02, 2021 | The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 4 similarly affected unrelated individuals (PMID:27454426, 27453715, 27173320, 24776766, 19451210, PM3_VS). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.0000636, PM2). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.899, 3Cnet: 0.995, PP3). Patient's phenotype is considered compatible with Gitelman syndrome (3billion dataset, PP4). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. - |
Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Apr 09, 2020 | Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as 5-Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0106 - This gene is known to be associated with autosomal recessive disease. (N) 0200 - Variant is predicted to result in a missense amino acid change from a threonine to a methionine (exon 1). (N) 0251 - Variant is heterozygous. (N) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (18 heterozygotes, 0 homozygotes). (P) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools and is highly conserved with a moderate amino acid change. (P) 0600 - Variant is located in an annotated domain or motif (AA permease N-terminal domain; PDB, DECIPHER). (N) 0801 - Strong previous evidence of pathogenicity in multiple unrelated individuals with Gitelman syndrome. (PMID: 22934535) (P) 0902 - Moderate evidence of variant segregating with disease in a family with 3 affected individuals (PMID: 18287808). (P) 1101 - Very strong and specific phenotype match. (P) 1201 - Heterozygous variant detected in trans with a second pathogenic heterozygous variant in a recessive disease (observed in IGV). (P) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Mar 26, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | The SLC12A3 c.179C>T (p.Thr60Met) missense variant is well described in the literature and noted to be one of the most common pathogenic variants associated with Gitelman syndrome in the Asian population (Shao et al. 2012). The p.Thr60Met variant is described in at least eight studies in which it is found in a total of 35 patients, including in ten individuals in a homozygous state, in 20 individuals in a compound heterozygous state, and in five in a heterozygous state (Maki et al. 2004; Shao et al. 2008; Qin et al. 2009; Miao et al. 2009; Jiang et al. 2014; Kim et al. 2016; Miao et al. 2016; Ma et al. 2016). The variant was detected in a heterozygous state in four out of 510 control individuals and is reported at a frequency of 0.00092 in the East Asian population of the Exome Aggregation Consortium. Functional studies in transgenic mice demonstrated that the p.Thr60Met variant resulted in reduced targeting to the apical membranes of distal convoluted tubule cells due to impaired phosphorylation of the Thr60 residue (Yang et al. 2013). Functional studies in Xenopus demonstrated that the variant showed the same pattern of complex glycosylation and similar cell surface expression as wild type but the intrinsic activity of the protein was abolished (Miao et al. 2009). Based on the collective evidence, the p.Thr60Met 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 | Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center | Aug 25, 2023 | PS3, PM2, PM3_Strong, PP3 - |
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 11, 2024 | This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 60 of the SLC12A3 protein (p.Thr60Met). This variant is present in population databases (rs371443644, gnomAD 0.08%). This missense change has been observed in individual(s) with Gitelman syndrome (PMID: 19207868, 19451210, 24776766, 27453715). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as c.185C>T (p.T60M). ClinVar contains an entry for this variant (Variation ID: 101514). 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: 19451210, 23833262). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Mar 21, 2014 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 27, 2022 | Reported multiple times in the homozygous or compound heterozygous state in unrelated patients with Gitelman syndrome (Maki et al., 2004; Lin et al., 2004; Lin et al., 2005; Shao et al., 2008a; Shao et al. 2008b; Qin et al., 2009; Miao et al., 2009; Jiang et al., 2014; Yang et al., 2013); Published functional studies demonstrate p.(T60M) results in nearly complete loss of intrinsic transporter activity (Miao et al., 2009); 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: 23833262, 25990047, 19207868, 27173320, 29093260, 30596175, 24776766, 27453715, 26825084, 27216017, 27454426, 18580052, 30413979, 31672324, 31398183, 33024574, 32884933, 33163079, 34348722, 27535533, 33735743, 22627394, 19451210, 15069170) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at