ClinVar Miner

Submissions for variant NM_000334.4(SCN4A):c.4949C>T (p.Pro1650Leu)

gnomAD frequency: 0.00002  dbSNP: rs774183791
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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 Inc RCV000713119 SCV000843690 uncertain significance not provided 2018-08-14 criteria provided, single submitter clinical testing
Invitae RCV001224260 SCV001396447 uncertain significance Hyperkalemic periodic paralysis 2019-10-18 criteria provided, single submitter clinical testing 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been observed in combination with a different SCN4A variant in a family with congenital myopathy (PMID: 30369941). ClinVar contains an entry for this variant (Variation ID: 586523). This variant is present in population databases (rs774183791, ExAC 0.001%). This sequence change replaces proline with leucine at codon 1650 of the SCN4A protein (p.Pro1650Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine.
GeneDx RCV000713119 SCV001830671 uncertain significance not provided 2020-03-27 criteria provided, single submitter clinical testing Observed in an individual with neuromuscular symptoms who harbored a second SCN4A variant (Theunissen 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: 32487525, 32129495, 30369941)
Fulgent Genetics, Fulgent Genetics RCV002493267 SCV002776152 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 2021-12-30 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV000713119 SCV004138783 uncertain significance not provided 2022-03-01 criteria provided, single submitter clinical testing SCN4A: PM2, PM3, PP3

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