ClinVar Miner

Submissions for variant NM_001161352.2(KCNMA1):c.3158A>G (p.Asn1053Ser) (rs886039469)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000255423 SCV000322055 pathogenic not provided 2017-09-11 criteria provided, single submitter clinical testing The N995S pathogenic variant in the KCNMA1 gene has been reported previously as a de novo variant in an individual with paroxysmal nonkinesigenic dyskinesia, paroxysmal dystonic postures, and mild developmental delay (Zhang et al., 2015). The N995S variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The N995S variant is a conservative amino acid substitution, which occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret N995S as a pathogenic variant.
Invitae RCV000504575 SCV000830549 pathogenic Paroxysmal nonkinesigenic dyskinesia, 3, with or without generalized epilepsy 2019-12-19 criteria provided, single submitter clinical testing This sequence change replaces asparagine with serine at codon 995 of the KCNMA1 protein (p.Asn995Ser). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and serine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to be de novo in individuals affected with epilepsy and/or paroxysomal dyskinesia (PMID: 26195193, 29330545, Invitae). This variant is also known as c.3158A>G (p.Asn1053Ser) in the literature. ClinVar contains an entry for this variant (Variation ID: 265313). Experimental studies have shown that this missense change results in increased channel activity and potassium current, consistent with a gain-of-function mechanism (PMID: 29330545). 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.
Undiagnosed Diseases Network,NIH RCV000504575 SCV000863433 pathogenic Paroxysmal nonkinesigenic dyskinesia, 3, with or without generalized epilepsy 2018-10-05 criteria provided, single submitter clinical testing
OMIM RCV000504575 SCV000598623 pathogenic Paroxysmal nonkinesigenic dyskinesia, 3, with or without generalized epilepsy 2017-08-30 no assertion criteria provided literature only

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