Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV002469973 | SCV002766019 | likely pathogenic | Familial hypokalemia-hypomagnesemia | 2022-10-31 | criteria provided, single submitter | clinical testing | Variant summary: The variant identified by MLPA or other technology involves the deletion of exons 1-6 and the partial deletion of exon 7 in the SLC12A3 gene. A presumed nomenclature of c.(?_-30)_885del has been designated for the purposes of this classification. Although exact breakpoints of this deletion are not known, it is expected to remove the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream site. An alternative downstream in-frame start codon (Met343) is located in exon 8 of the encoded protein. An activation of this potential downstream translation initiation site would result in a shortened protein missing the first 342 amino acids from the protein sequence, resulting in a large deletion in the SLC12A3 gene, a known mechanism of disease. Multiple variants located upstream of this alternate initiation codon, including several ones affecting the canonical initiation codon, have been reported as pathogenic/disease-causing in ClinVar/HGMD. The variant was absent in 21694 control chromosomes (gnomAD, Structural Variants dataset). To our knowledge, no occurrence of c.(?_-30)_885del in individuals affected with Familial Hypokalemia-Hypomagnesemia (Gitelman syndrome) and no experimental evidence demonstrating its impact on protein function have been reported. Nevertheless, deletion of exons 1-7 and deletion of exons 1-6 has been reported in the literature in multiple individuals affected with Gitelman Syndrome (PMIDs: 11168953, 22009145). One clinical diagnostic laboratory has submitted a clinical-significance assessment for a similar variant to ClinVar after 2014, which also involves the deletion of exons 1-6 and the partial deletion of exon 7 (Variation ID: 945564), and classified that variant as pathogenic. Based on the evidence outlined above, c.(?_-30)_885del was classified as likely pathogenic. |