ClinVar Miner

Submissions for variant NM_000334.4(SCN4A):c.3386G>A (p.Arg1129Gln) (rs527236149)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000395392 SCV000336025 uncertain significance not provided 2015-09-29 criteria provided, single submitter clinical testing
GeneReviews RCV000132736 SCV000187697 pathogenic Hypokalemic periodic paralysis, type 2 2014-07-31 no assertion criteria provided literature only
Invitae RCV000547264 SCV000658558 uncertain significance Hyperkalemic Periodic Paralysis Type 1 2018-11-12 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 1129 of the SCN4A protein (p.Arg1129Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs527236149, ExAC 0.06%). This variant has been reported to segregate with disease in a single family affected with both hypokalaemic and normokalaemic periodic paralysis (PMID: 20522878). ClinVar contains an entry for this variant (Variation ID: 143200). This variant identified in the SCN4A gene is located in the Voltage-sensor S4 of repeat III region of the resulting protein (PMID:25348405). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. In summary, this variant is a rare missense change with uncertain impact on protein function. Because it is found in the population at an appreciable frequency, this variant is not anticipated to cause disease. However, the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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