Submissions for variant NM_001161352.2(KCNMA1):c.3673C>T (p.Arg1225Trp)

gnomAD frequency: 0.00003  dbSNP: rs148648986

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001052247	SCV001216448	uncertain significance	Generalized epilepsy-paroxysmal dyskinesia syndrome	2023-11-28	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1167 of the KCNMA1 protein (p.Arg1167Trp). This variant is present in population databases (rs148648986, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with KCNMA1-related conditions. ClinVar contains an entry for this variant (Variation ID: 848479). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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	RCV001052247	SCV001260927	uncertain significance	Generalized epilepsy-paroxysmal dyskinesia syndrome	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
GeneDx	RCV001571855	SCV001796399	uncertain significance	not provided	2023-01-03	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
PreventionGenetics, part of Exact Sciences	RCV003405257	SCV004114791	uncertain significance	KCNMA1-related condition	2023-04-04	criteria provided, single submitter	clinical testing	The KCNMA1 c.3499C>T variant is predicted to result in the amino acid substitution p.Arg1167Trp. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.013% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/10-78647062-G-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.