ClinVar Genomic variation as it relates to human health

The SLC12A3 c.1946C>T (p.Thr649Met) variant is a missense variant that has been reported in at least four unrelated individuals with Gitelman syndrome, including in a homozygous state in one individual, in a compound heterozygous state in two individuals, and in a heterozygous state in one individual in whom a second variant was not identified (Lemmink et al. 1998; Ji et al. 2008; Sung et al. 2011; Yang et al. 2018). The variant co-segregated with the disease in the family of the homozygous individual, with four affected siblings also found to be homozygous for the variant. The proband of this family was also heterozygous for another missense variant (Lemmink et al. 1998). In addition, the mother of one of the compound heterozygotes, who had asymptomatic hypokalemia, hypomagnesemia, and hypocalciuria, was also compound heterozygous, carrying the p.Thr649Met variant and a different variant in trans. The p.Thr649Met variant, which affects a conserved residue, was absent from 50 control chromosomes but is reported at a frequency of 0.000682 in the African American population of the Exome Sequencing Project. Based on the collective evidence, the p.Thr649Met variant is classified as likely pathogenic for Gitelman syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

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. Computational tools predict that this variant is damaging.

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 649 of the SLC12A3 protein (p.Thr649Met). This variant is present in population databases (rs145337602, gnomAD 0.04%). This missense change has been observed in individual(s) with Gitelman syndrome (PMID: 21256383, 21415153). 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.1945G>A Thr649Met. ClinVar contains an entry for this variant (Variation ID: 632259). 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.Thr649 amino acid residue in SLC12A3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9734597, 12039972, 25841442). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

The SLC12A3 c.1946C>T variant is predicted to result in the amino acid substitution p.Thr649Met. This variant, also referred to as c.1945G>A (p.Thr649Met), has been reported as causative for Gitelman syndrome in multiple individuals (as T649M, Table S3, Ji et al. 2008. PubMed ID: 18391953; Sung et al. 2011. PubMed ID: 21256383; Xia et al. 2017. PubMed ID: 28469853; Zeng et al. 2019. PubMed ID: 31398183). This variant is reported in 0.040% of alleles in individuals of African descent in gnomAD. This variant is interpreted as pathogenic.