ClinVar Miner

Submissions for variant NM_001126108.2(SLC12A3):c.460A>T (p.Ile154Phe)

gnomAD frequency: 0.00001  dbSNP: rs748547209
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000493117 SCV000582437 uncertain significance not provided 2023-03-27 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 11168953, 36351028, 34604727, 25841442)
Fulgent Genetics, Fulgent Genetics RCV002506193 SCV002795074 likely pathogenic Familial hypokalemia-hypomagnesemia 2022-04-18 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000493117 SCV003443557 likely pathogenic not provided 2023-12-06 criteria provided, single submitter clinical testing This sequence change replaces isoleucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 154 of the SLC12A3 protein (p.Ile154Phe). This variant is present in population databases (rs748547209, gnomAD 0.004%). This missense change has been observed in individuals with Gitelman syndrome (PMID: 11168953, 25841442). ClinVar contains an entry for this variant (Variation ID: 429782). 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%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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