ClinVar Miner

Submissions for variant NM_000334.4(SCN4A):c.4420G>A (p.Ala1474Thr)

gnomAD frequency: 0.00001  dbSNP: rs778417596
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics RCV000713113 SCV000843684 uncertain significance not provided 2018-06-06 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001053863 SCV001218146 uncertain significance Hyperkalemic periodic paralysis 2023-12-11 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1474 of the SCN4A protein (p.Ala1474Thr). This variant is present in population databases (rs778417596, gnomAD 0.03%). 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: 586520). 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. 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.
Illumina Laboratory Services, Illumina RCV000713113 SCV003802863 uncertain significance not provided 2022-11-30 criteria provided, single submitter clinical testing The SCN4A c.4420G>A (p.Ala1474Thr) missense variant results in the substitution of alanine at amino acid position 1474 with threonine. The c.4420G>A variant has been reported in a heterozygous state in one individual who was presumed to be affected, however, no clinical information was provided (PMID: 33726816). This variant is reported in the Genome Aggregation Database in eight alleles at a frequency of 0.000436 in the East Asian population (version 2.1.1). Multiple lines of computational evidence suggest the variant may have a deleterious effect on the gene or gene product. Based on the available evidence, the c.4420G>A (p.Ala1474Thr) variant is classified as a variant of uncertain significance for SCN4A-related channelopathies.
Revvity Omics, Revvity RCV000713113 SCV003818709 uncertain significance not provided 2020-06-19 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV005021115 SCV005651706 uncertain significance Potassium-aggravated myotonia; Paramyotonia congenita of Von Eulenburg; Hypokalemic periodic paralysis, type 2; Hyperkalemic periodic paralysis; Congenital myasthenic syndrome 16; Congenital myopathy 22A, classic; Congenital myopathy 22B, severe fetal 2024-03-12 criteria provided, single submitter clinical testing

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