ClinVar Miner

Submissions for variant NM_001126108.2(SLC12A3):c.938C>T (p.Ala313Val)

gnomAD frequency: 0.00004  dbSNP: rs140551719
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics RCV000516845 SCV000615296 likely pathogenic not provided 2016-08-16 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000516845 SCV001384810 pathogenic not provided 2024-05-13 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 313 of the SLC12A3 protein (p.Ala313Val). This variant is present in population databases (rs140551719, gnomAD 0.004%). This missense change has been observed in individual(s) with Gitelman syndrome (PMID: 11168953, 15824853, 21415153, 22009145). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 448400). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SLC12A3 protein function. For these reasons, this variant has been classified as Pathogenic.
Genome-Nilou Lab RCV001274377 SCV002055329 likely pathogenic Familial hypokalemia-hypomagnesemia 2021-07-15 criteria provided, single submitter clinical testing
European Hospital Georges Pompidou Genetics Department, Assistance Publique - Hôpitaux de Paris AP-HP RCV001274377 SCV002513798 likely pathogenic Familial hypokalemia-hypomagnesemia 2022-04-27 criteria provided, single submitter clinical testing ACMG criteria used:PS4 PM1 PM2 PP5
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute RCV001274377 SCV002767446 pathogenic Familial hypokalemia-hypomagnesemia 2021-05-06 criteria provided, single submitter clinical testing Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Gitelman syndrome (MIM#263800). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from alanine to valine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 6 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated AA_permease domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in at least ten Gitelman Syndrome patients both as homozygous and compound heterozygous (PMID: 25012174, 22009145, 21415153, ClinVar). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Fulgent Genetics, Fulgent Genetics RCV001274377 SCV002809699 likely pathogenic Familial hypokalemia-hypomagnesemia 2024-01-16 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV003409740 SCV004114920 pathogenic SLC12A3-related disorder 2023-02-17 criteria provided, single submitter clinical testing The SLC12A3 c.938C>T variant is predicted to result in the amino acid substitution p.Ala313Val. This variant has been reported in the homozygous or compound heterozygous state in patients with Gitelman syndrome (Table S1a, Vargas-Poussou et al. 2011. PubMed ID: 21415153; Cruz et al. 2001. PubMed ID: 11168953; Table S1, Hureaux et al. 2019. PubMed ID: 31672324). This variant is reported in 0.0040% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-56906348-C-T). This variant is interpreted as pathogenic.
Natera, Inc. RCV001274377 SCV001458489 likely pathogenic Familial hypokalemia-hypomagnesemia 2020-09-16 no assertion criteria provided clinical testing

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