ClinVar Miner

Submissions for variant NM_000334.4(SCN4A):c.3395G>A (p.Arg1132Gln) (rs80338789)

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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 RCV000517960 SCV000615083 pathogenic not provided 2016-09-01 criteria provided, single submitter clinical testing
Invitae RCV000692011 SCV000819816 pathogenic Hyperkalemic Periodic Paralysis Type 1 2019-09-04 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 1132 of the SCN4A protein (p.Arg1132Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to segregate with hypokalemic periodic paralysis in families (PMID: 16890191, 19882638) and has been reported in individuals with hypokalemic periodic paralysis (PMID: 16890191, 19118277). ClinVar contains an entry for this variant (Variation ID: 21155). Experimental studies have shown that this missense change results in an ion channel with altered properties (PMID: 16890191, 21490317). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV001174896 SCV001338320 pathogenic not specified 2020-02-20 criteria provided, single submitter clinical testing Variant summary: SCN4A c.3395G>A (p.Arg1132Gln) results in a conservative amino acid change located in the Ion transport domain (IPR005821) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 249412 control chromosomes (gnomAD). c.3395G>A has been reported in the literature in multiple individuals including one homozygote affected with SCN4A-Related Disorders (Carle_2006, Matthews_2009, Arzel-Hezode_2010). These data indicate that the variant is very likely to be associated with disease. At least two functional studies report this variant conducts an anomalous gating pore current (Carle_2006, Francis_2011). Two ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
GeneReviews RCV000020270 SCV000040624 pathologic Hypokalemic periodic paralysis 1 2009-04-28 no assertion criteria provided curation Converted during submission to Pathogenic.
OMIM RCV000043510 SCV000067380 pathogenic Hypokalemic periodic paralysis, type 2 2011-05-10 no assertion criteria provided literature only

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