| Date | Panel | Item | Activity | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Early onset or syndromic epilepsy v2.249 | KCNMA1 | Arina Puzriakova Phenotypes for gene: KCNMA1 were changed from ?Cerebellar atrophy, developmental delay, and seizures, 617643; Paroxysmal nonkinesigenic dyskinesia, 3, with or without generalized epilepsy, 609446 to Cerebellar atrophy, developmental delay, and seizures, OMIM:617643; Cerebellar atrophy, developmental delay, and seizures, MONDO:0060551; Paroxysmal nonkinesigenic dyskinesia, 3, with or without generalized epilepsy, OMIM:609446; Generalized epilepsy-paroxysmal dyskinesia syndrome, MONDO:0012276; Liang-Wang syndrome, OMIM:618729; Liang-Wang syndrome, MONDO:0032886; {Epilepsy, idiopathic generalized, susceptibility to, 16}, OMIM:618596; Epilepsy, idiopathic generalized, susceptibility to, 16, MONDO:0032827 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v2.248 | KCNMA1 | Arina Puzriakova Publications for gene: KCNMA1 were set to 15937479; 26195193; 27567911; 29545233; 27567911 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v1.266 | KCNMA1 | Rebecca Foulger Marked gene: KCNMA1 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v1.266 | KCNMA1 | Rebecca Foulger Gene: kcnma1 has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v1.266 | KCNMA1 | Rebecca Foulger Classified gene: KCNMA1 as Green List (high evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v1.266 | KCNMA1 | Rebecca Foulger Added comment: Comment on list classification: Updated rating of KCNMA1 from Amber to Green based on post-Webex reviews from Helen Lord, Allison Callaway and Konstantinos Varvagiannis. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v1.266 | KCNMA1 | Rebecca Foulger Gene: kcnma1 has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v1.265 | KCNMA1 | Rebecca Foulger Added comment: Comment on mode of inheritance: Kept Mode of Inheritance as 'BOTH monoallelic and biallelic' based on post-Webex reviews from Helen Lord and Konstantinos Varvagiannis. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v1.265 | KCNMA1 | Rebecca Foulger Mode of inheritance for gene: KCNMA1 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v1.262 | KCNMA1 | Rebecca Foulger commented on gene: KCNMA1: Review and rating collated by Helen Lord (Oxford University Hospitals NHS Foundation Trust, 2019_08_30) on behalf of West Midlands, Oxford and Wessex GLH for GMS Neurology specialist test group. This gene is part of a subset that were re-reviewed following the group Webex call on 2019_08_08 for Clinical Indication R59 Early onset or syndromic epilepsy. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v1.261 | KCNMA1 | Helen Lord reviewed gene: KCNMA1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v1.256 | KCNMA1 |
Konstantinos Varvagiannis changed review comment from: In a recent extensive review of the literature, Bailey et al. (2019 - PMID: 31427379) summarize the phenotype of KCNMA1-related channelopathy. Overall the features of 37 subjects with 16 KCNMA1 pathogenic variants are discussed in detail. [An also relevant report by Liang et al. published in 6/2019 - PMID: 31152168 - was also considered for this review]. KCNMA1 encodes the pore-forming α subunit of large-conductance voltage- and Ca(2+)-activated K+ channel (also called BK channel). BK channels have highest expression levels in brain (acting as regulators of neuronal exciatbility) and muscle. Variants in the review are distinguished in GoF, LoF and VUS (the latter used for variants of unknown/uncharacterized effect on BK channel activity) [NM_002247.3 mentioned as RefSeq]: - GoF variants included D434G (a variant reported in 13 individuals) and N995S (also reported as N999S or N1053S). - LoF variants included S351Y, G356R, G375R, N449fs*, I663V, C413Y, P805L, D984N, G354S. - Uncharacterized variants included R458Ter, Y676Lfs*7 (both presumed to result to LoF), K518N, E656A, N1195S, E884K. The disorder exhibited in most cases aut. dominant inheritance (either as de novo occurrence of a variant or identification in successive generations), with autosomal recessive inheritance reported in one pedigree (sibs with Y676Lfs*fs) (Tabarki et al. 2016 - PMID: 27567911). As the authors comment, the hallmark of KCNMA1-related channelopathy is neurological dysfunction incl. seizures, movement disorders, DD and ID. Epilepsy was a feature in approx. half individuals (18/37) irrespective of mutation type (eg. 9/20 in the case of GoF, 6/13 in LoF variants). Seizure characteristics were highly variable as for the onset, type, EEG pattern, frequency/duration and response to medication. Overlapping types were noted for GoF and LoF mutations incl. myoclonic, GTCS, absence seizures with few being more frequent or specific in certain mutation types. Individuals with the same variant may present or not certain features eg. 6/13 members of a large family with D434G or 3/7 (all unrelated) individuals with N1053S developed epilepsy. Animal studies support a role for both LoF and GoF alterations in BK channel activity as for the seizures, with more solid evidence/correlation with GoF mutations. (Other phenotypes eg. movement disorders are also supported by animal models). Similarly developmental delay has been reported in 21/37 individuals and intellectual disability in 12/37 (both GoF and LoF) with severe presentation in certain cases (eg. in 3 individuals with G375R) while on several occasions severity (or presence of this feature(?)) has probably not been commented on. The KCNMA1-related disorders in OMIM are the following: ?Cerebellar atrophy, developmental delay, and seizures, 617643 (AR) Paroxysmal nonkinesigenic dyskinesia, 3, with or without generalized epilepsy, 609446 (AD) KCNMA1 is part of the DD panel of G2P associated with Generalized epilepsy and paroxysmal dyskinesia (monoallelic, activating mutations / disease confidence : possible). KCNMA1 is included in several gene panels for epilepsy incl. those of Radboudumc and Victorian Clinical Genetics and several other panels summarized in the supplement of the review. The gene is included in gene panels for ID offered by some diagnostic laboratories (eg. GeneDx). As a result upgrade to green rating can be considered for the epilepsy panel. The gene could possibly be upgraded to amber (or green) in the ID panel, too.; to: In a recent extensive review of the literature, Bailey et al. (2019 - PMID: 31427379) summarize the phenotype of KCNMA1-related channelopathy. Overall the features of 37 subjects with 16 KCNMA1 pathogenic variants are discussed in detail. [An also relevant report by Liang et al. published in 6/2019 - PMID: 31152168 - was also considered for this review]. KCNMA1 encodes the pore-forming α subunit of large-conductance voltage- and Ca(2+)-activated K+ channel (also called BK channel). BK channels have highest expression levels in brain (acting as regulators of neuronal exciatbility) and muscle. Variants in the review are distinguished in GoF, LoF and VUS (the latter used for variants of unknown/uncharacterized effect on BK channel activity) [NM_002247.3 mentioned as RefSeq]: - GoF variants included D434G (a variant reported in 13 individuals) and N995S (also reported as N999S or N1053S). - LoF variants included S351Y, G356R, G375R, N449fs*, I663V, C413Y, P805L, D984N, G354S. - Uncharacterized variants included R458Ter, Y676Lfs*7 (both presumed to result to LoF), K518N, E656A, N1195S, E884K. The disorder exhibited in most cases aut. dominant inheritance (either as de novo occurrence of a variant or identification in successive generations), with autosomal recessive inheritance reported in one pedigree (sibs with Y676Lfs*fs) (Tabarki et al. 2016 - PMID: 27567911). As the authors comment, the hallmark of KCNMA1-related channelopathy is neurological dysfunction incl. seizures, movement disorders, DD and ID. Epilepsy was a feature in approx. half individuals (18/37) irrespective of mutation type (eg. 9/20 in the case of GoF, 6/13 in LoF variants). Seizure characteristics were highly variable as for the onset, type, EEG pattern, frequency/duration and response to medication. Overlapping types were noted for GoF and LoF mutations incl. myoclonic, GTCS, absence seizures with few being more frequent or specific in certain mutation types. Individuals with the same variant may present or not certain features eg. 6/13 members of a large family with D434G or 3/7 (all unrelated) individuals with N1053S developed epilepsy. Animal studies support a role for both LoF and GoF alterations in BK channel activity as for the seizures, with more solid evidence/correlation with GoF mutations. (Other phenotypes eg. movement disorders are also supported by animal models). Similarly developmental delay has been reported in 21/37 individuals and intellectual disability in 12/37 (both GoF and LoF) with severe presentation in certain cases (eg. in 3 individuals with G375R) while on several occasions severity (or presence of this feature(?)) has probably not been commented on. The KCNMA1-related disorders in OMIM are the following : ?Cerebellar atrophy, developmental delay, and seizures, 617643 (AR) Paroxysmal nonkinesigenic dyskinesia, 3, with or without generalized epilepsy, 609446 (AD) KCNMA1 is part of the DD panel of G2P associated with Generalized epilepsy and paroxysmal dyskinesia (monoallelic, activating mutations / disease confidence : possible). KCNMA1 is included in several gene panels for epilepsy incl. those of Radboudumc and Victorian Clinical Genetics and several other panels summarized in the supplement of the review. The gene is included in gene panels for ID offered by some diagnostic laboratories (eg. GeneDx). As a result upgrade to green rating can be considered for the epilepsy panel. The gene could possibly be upgraded to amber (or green) in the ID panel, too. |
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| Early onset or syndromic epilepsy v1.256 | KCNMA1 | Konstantinos Varvagiannis reviewed gene: KCNMA1: Rating: GREEN; Mode of pathogenicity: None; Publications: 31427379, 31152168, 27567911; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v1.256 | KCNMA1 | Alison Callaway reviewed gene: KCNMA1: Rating: GREEN; Mode of pathogenicity: None; Publications: 29933521; Phenotypes: Generalised epilepsy and paroxysmal dyskinesia; Mode of inheritance: None | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v1.191 | KCNMA1 | Rebecca Foulger Source Wessex and West Midlands GLH was added to KCNMA1. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v1.190 | KCNMA1 | Rebecca Foulger Source NHS GMS was added to KCNMA1. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v1.189 | KCNMA1 | Rebecca Foulger edited their review of gene: KCNMA1: Added comment: Review and rating collated by Tracy Lester (Oxford Medical Genetics Laboratories Oxford University Hospitals NHS Foundation Trust, 2019_02_06) on behalf of Wessex and West Midlands GLH for GMS Neurology specialist test group, for Clinical Indication R59 'Early onset or syndromic epilepsy'. Review contributors: Alison Callaway and John Taylor. Suggested gene rating: Amber. ; Changed rating: AMBER | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v1.188 | KCNMA1 | Tracy Lester reviewed gene: KCNMA1: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ?Cerebellar atrophy developmental delay and seizures, 617643, Paroxysmal nonkinesigenic dyskinesia 3 with or without generalized epilepsy, 609446; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v1.132 | KCNMA1 | Rebecca Foulger Added comment: Comment on phenotypes: MIM:617643 has AR inheritance in OMIM. MIM:609446 has monoallelic inheritance in OMIM. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v1.132 | KCNMA1 | Rebecca Foulger Phenotypes for gene: KCNMA1 were changed from ?Cerebellar atrophy, developmental delay, and seizures 617643 AR; Paroxysmal nonkinesigenic dyskinesia, 3, with or without generalized epilepsy 609446 AD to ?Cerebellar atrophy, developmental delay, and seizures, 617643; Paroxysmal nonkinesigenic dyskinesia, 3, with or without generalized epilepsy, 609446 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v1.131 | KCNMA1 | Rebecca Foulger Publications for gene: KCNMA1 were set to 15937479; 26195193; 27567911 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v1.130 | KCNMA1 | Rebecca Foulger commented on gene: KCNMA1: PMID:29545233. Yesil et al., 2018 report a patient with a novel homozygous truncating variant in KCNMA1 (p.Arg458Ter) presentint with paroxysmal dyskinesia, epileptic seizures, ID, and corticospinal–cerebellar tract atrophy. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v1.130 | KCNMA1 | Rebecca Foulger commented on gene: KCNMA1: PMID:15937479. Du et al., 2005 studied a large family with generalized epilepsy and paroxysmal dyskinesia (GEPD). 5/16 had seizures + paroxysmal dyskinesia (PNKD), and a further 4/16 had seizures only. c.1301A>G (Asp434Gly). They identified a heterozygous c.1301A>G (Asp434Gly) in KCNMA1 in the proband (IV-8) of the family and in all 13 affected individuals that were genotyped. The variant was absent in 5 unaffected individuals. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v1.130 | KCNMA1 | Rebecca Foulger commented on gene: KCNMA1: PMID:26195193. Zhang et al 2015 describe 2 unrelated children with early-onset PNKD and developmental delay carrying de novo mutations in KCNMA1. Seizures were not reported until age 2 and 7. Two de novo heterozygous missense mutations in KCNMA1 were identified in these cases: c.2650G>A (p.Glu884Lys) and c.3158A>G (p.Asn1053Ser). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v1.130 | KCNMA1 | Rebecca Foulger commented on gene: KCNMA1 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v1.21 | KCNMA1 | Deb Pal reviewed gene: KCNMA1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v0.503 | KCNMA1 | Louise Daugherty Added comment: Comment on publications: added new publication | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v0.503 | KCNMA1 | Louise Daugherty Publications for gene: KCNMA1 were set to 15937479; 26195193; 27567911 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v0.473 | KCNMA1 | Sarah Leigh Marked gene: KCNMA1 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v0.473 | KCNMA1 | Sarah Leigh Gene: kcnma1 has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy | KCNMA1 | Zornitza Stark reviewed gene: KCNMA1 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy | KCNMA1 | Sarah Leigh classified KCNMA1 as Red List (low evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy | KCNMA1 | Sarah Leigh Added gene to panel | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||