ClinVar Miner

Submissions for variant NM_000334.4(SCN4A):c.4484T>C (p.Ile1495Thr)

gnomAD frequency: 0.00001  dbSNP: rs1318966106
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000809929 SCV000950112 pathogenic Hyperkalemic periodic paralysis 2023-09-29 criteria provided, single submitter clinical testing This variant is not present in population databases (gnomAD no frequency). This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1495 of the SCN4A protein (p.Ile1495Thr). This missense change has been observed in individuals with clinical features of periodic paralysis (PMID: 23884711; Invitae). ClinVar contains an entry for this variant (Variation ID: 654042). 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 SCN4A protein function. This variant disrupts the p.Ile1495 amino acid residue in SCN4A. Other variant(s) that disrupt this residue have been observed in individuals with SCN4A-related conditions (PMID: 10366610, 33123387), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Athena Diagnostics Inc RCV001664430 SCV001879497 uncertain significance not provided 2023-06-26 criteria provided, single submitter clinical testing Available data are insufficient to determine the clinical significance of the variant at this time. This variant is statistically more frequent in patients than in the general population (http://gnomad.broadinstitute.org). This variant has been identified in multiple individuals with clinical features associated with this gene. At least one other missense variant at this codon is considered to be pathogenic or likely pathogenic, suggesting this variant may also cause disease. This variant has been seen where an alternate explanation for disease was also identified, suggesting this variant may not cause disease. Computational tools disagree on the variant's effect on normal protein function.
GeneDx RCV001664430 SCV002538821 likely pathogenic not provided 2022-06-21 criteria provided, single submitter clinical testing Observed in an individual with hyperkalemic periodic paralysis, but no additional information was provided (Charles et al., 2013); Not observed at significant frequency in large population cohorts (gnomAD); 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: 23884711, 27535533)
Revvity Omics, Revvity RCV001664430 SCV003823202 uncertain significance not provided 2019-03-06 criteria provided, single submitter clinical testing

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