ClinVar Miner

Submissions for variant NM_000334.4(SCN4A):c.679C>T (p.Leu227Phe)

gnomAD frequency: 0.00006  dbSNP: rs368999500
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001954125 SCV002239776 uncertain significance Hyperkalemic periodic paralysis 2024-05-24 criteria provided, single submitter clinical testing This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 227 of the SCN4A protein (p.Leu227Phe). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with SCN4A-related conditions. ClinVar contains an entry for this variant (Variation ID: 1461866). 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 SCN4A protein function. Experimental studies have shown that this missense change does not substantially affect SCN4A function (PMID: 29605429). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx RCV002276958 SCV002567701 uncertain significance not provided 2022-07-26 criteria provided, single submitter clinical testing Reported previously in a control individual in a study regarding sudden infantile death syndrome (Mnnikk et al., 2018); 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: 29605429)
Fulgent Genetics, Fulgent Genetics RCV002492144 SCV002792063 uncertain significance Hypokalemic periodic paralysis, type 1; Potassium-aggravated myotonia; Paramyotonia congenita of Von Eulenburg; Hypokalemic periodic paralysis, type 2; Hyperkalemic periodic paralysis; Congenital myasthenic syndrome 16 2022-02-15 criteria provided, single submitter clinical testing

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