Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP2
The NM_001161352.2(KCNMA1):c.3653G>A(p.Arg1218Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000958 in 1,461,884 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).
KCNMA1 (HGNC:6284): (potassium calcium-activated channel subfamily M alpha 1) This gene encodes the alpha subunit of calcium-activated BK channel. The encoded protein is involved in several physiological processes including smooth muscle contraction, neurotransmitter release and neuronal excitability. Mutations in this gene are associated with a spectrum of neurological disorders including Paroxysmal Nonkinesigenic Dyskinesia 3, Idiopathic Generalized Epilepsy 16 and Liang-Wang syndrome. [provided by RefSeq, Aug 2022]
Verdict is Uncertain_significance. Variant got 1 ACMG points.
PP2
Missense variant in the KCNMA1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 12 curated pathogenic missense variants (we use a threshold of 10). The gene has 25 curated benign missense variants. Gene score misZ: 5.0622 (above the threshold of 3.09). Trascript score misZ: 6.5162 (above the threshold of 3.09). GenCC associations: The gene is linked to cerebellar atrophy, developmental delay, and seizures, generalized epilepsy-paroxysmal dyskinesia syndrome, Liang-Wang syndrome.
Review Status: criteria provided, single submitter
Collection Method: clinical testing
The R1160Q variant in the KCNMA1 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The R1160Q 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 R1160Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret R1160Q as a variant of uncertain significance. -
Review Status: criteria provided, single submitter
Collection Method: clinical testing
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1160 of the KCNMA1 protein (p.Arg1160Gln). This variant is present in population databases (rs200723995, gnomAD 0.003%). 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: 373537). 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 tolerated. 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. -
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