Submissions for variant NM_001161352.2(KCNMA1):c.2660A>G (p.Lys887Arg)

gnomAD frequency: 0.00001  dbSNP: rs753684298

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000768247	SCV000898774	uncertain significance	Generalized epilepsy-paroxysmal dyskinesia syndrome; Cerebellar atrophy, developmental delay, and seizures	2017-10-10	criteria provided, single submitter	clinical testing	KCNMA1 NM_002247.3 exon 21 p.Lys829Arg (c.2486A>G): This variant has not been reported in the literature but is present in 2/111576 European alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs753684298). This variant amino acid Arginine (Arg) is present in >20 bird, reptile and fish species; this suggests that this variant may not impact the protein. Additional computational prediction tools are unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001869059	SCV002136782	uncertain significance	Generalized epilepsy-paroxysmal dyskinesia syndrome	2024-02-12	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 829 of the KCNMA1 protein (p.Lys829Arg). This variant is present in population databases (rs753684298, gnomAD 0.002%). 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: 626124). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt KCNMA1 protein function with a negative predictive value of 80%. 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.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV003224444	SCV003920100	uncertain significance	Generalized epilepsy-paroxysmal dyskinesia syndrome; Cerebellar atrophy, developmental delay, and seizures; Epilepsy, idiopathic generalized, susceptibility to, 16; Liang-Wang syndrome	2021-03-30	criteria provided, single submitter	clinical testing	KCNMA1 NM_002247 exon 21 p.Lys829Arg (c.2486A>G): This variant has not been reported in the literature but is present in 2/111576 European alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs753684298). This variant amino acid Arginine (Arg) is present in >20 bird, reptile and fish species; this suggests that this variant may not impact the protein. Additional computational prediction tools are unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
GeneDx	RCV004797869	SCV005419770	uncertain significance	not provided	2024-05-28	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge