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| Early onset or syndromic epilepsy v2.517 | CACNA2D1 | Sarah Leigh reviewed gene: CACNA2D1: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v2.517 | CACNA2D1 | Sarah Leigh Classified gene: CACNA2D1 as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v2.517 | CACNA2D1 | Sarah Leigh Gene: cacna2d1 has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v2.516 | CACNA2D1 | Sarah Leigh Publications for gene: CACNA2D1 were set to 35293990 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v2.503 | CACNA2D1 | Konstantinos Varvagiannis reviewed gene: CACNA2D1: Rating: AMBER; Mode of pathogenicity: None; Publications: 35293990, 28097321; Phenotypes: Abnormal muscle tone, Feeding difficulties, Global developmental delay, Intellectual disability, Seizures, Microcephaly, Abnormality of the corpus callosum, Cerebral atrophy, Abnormality of movement, Cortical visual impairment, Pain insensitivity; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v2.500 | CACNA2D1 |
Helen Lord changed review comment from: Dahimne et al, 2022, 35293990 - two unrelated patients with biallelic CACNA2D1 variants - trio exome sequencing - identified by gene matcher. Patient 1: homozygous fs variant c.818_821dup p.(Ser275fs) - healthy parents het carriers. Patient 2: compound het for a fs c.13_23dup p.(Leu9fs) and a missense variant c.626G>A p.(Gly209Asp) - parents healthy carriers of each of the variants. Both individuals show a highly consistent phenotype, corresponding to DEE - microcephalic, severe hypotonia, absent speech, spasticity, choreiform movements, orofacial dyskinesia and cortical visual impairement. Brain imaging showed corpus callosum hypoplasia and progressive volume loss in both. Both patients also showed insensitivity to pain. Looking at mRNA level in patient fibroblasts in both patients showed it was reduced to 6-9% compared to control fibroblasts. Also data suggest the fs variants result in LOF. Gly209 - this Gly is important for maintaining a 3-strand-beta-sheet-stability and simultaneously provididn ga critial turn in the structure and is absoloutely invariant in both CACNA2D1 and CACNA2D2 orthologs in all vertebrates and paralogs and predecessors from low invertebrates. Functional work on the missense change shows it disrupts plasma membrane a2d-1 expression by 86.2% compared to wt. It abolishes the ability of a2d-1 to promote Cav2.2 currents, it does not promote Cav2.2 cell surface expression or trafficking in hippocampal neurons and it shows reduced complex formation with Cav2.2 and limited proteolytic cleavage. Suggests the HA-a2b-1 with the G209D variant remains largely as the uncleaved imaature form, indicating that it probably remains in the endoplasmic reticulum - suggests LOF effect. Sources: NHS GMS; to: Dahimne et al, 2022, 35293990 - two unrelated patients with biallelic CACNA2D1 variants - trio exome sequencing - identified by gene matcher. Patient 1: homozygous fs variant c.818_821dup p.(Ser275fs) - healthy parents het carriers. Patient 2: compound het for a fs c.13_23dup p.(Leu9fs) and a missense variant c.626G>A p.(Gly209Asp) - parents healthy carriers of each of the variants. Both individuals show a highly consistent phenotype, corresponding to DEE - microcephalic, severe hypotonia, absent speech, spasticity, choreiform movements, orofacial dyskinesia and cortical visual impairement. Brain imaging showed corpus callosum hypoplasia and progressive volume loss in both. Both patients also showed insensitivity to pain. Looking at mRNA level in patient fibroblasts in both patients showed it was reduced to 6-9% compared to control fibroblasts. Also data suggest the fs variants result in LOF. Gly209 - this Gly is important for maintaining a 3-strand-beta-sheet-stability and simultaneously providing a critial turn in the structure and is absoloutely invariant in both CACNA2D1 and CACNA2D2 orthologs in all vertebrates and paralogs and predecessors from low invertebrates. Functional work on the missense change shows it disrupts plasma membrane a2d-1 expression by 86.2% compared to wt. It abolishes the ability of a2d-1 to promote Cav2.2 currents, it does not promote Cav2.2 cell surface expression or trafficking in hippocampal neurons and it shows reduced complex formation with Cav2.2 and limited proteolytic cleavage. Suggests the HA-a2b-1 with the G209D variant remains largely as the uncleaved imaature form, indicating that it probably remains in the endoplasmic reticulum - suggests LOF effect. Sources: NHS GMS |
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| Early onset or syndromic epilepsy v2.500 | CACNA2D1 |
Helen Lord changed review comment from: Dahimne et al, 2022, 35293990 - two unrelated patients with biallelic CACNA2D1 variants - trio exome sequencing - identified by gene matcher. Patient 1: homozygous fs variant c.818_821dup p.(Ser275fs) - healthy parents het carriers. Patient 2: compound het for a fs c.13_23dup p.(Leu9fs) and a missense variant c.626G>A p.(Gly209Asp) - parents healthy carriers of each of the variants. Both individuals show a highly conssitent phenotype, corresponding to DEE - microcephalic, severe hypotonia, absent speech, spasticity, choreiform movements, orofacial dyskinesia and cortical visual impairement. Brain imaging showed corpus callosum hypoplasia and progressive volume loss in both. Both patients also showed insensitivty to apin Looking at mRNA level in patient fibroblasts in both pTIWNTS showed it was reduced to 6-9% compared to control fibroblasts. Also data suggest the fs variants result in LOF. Gly209 - this Gly is importnat for maintaining a 3-strand-beta-sheet-stability and simultaneously provididn ga critial turn in the structure and is absoloutely invariant in both CACNA2D1 and CACNA2D2 orthologs in all vertebrates and paralogs and predecessors from low invertebrates. Functional work on the missense change shows it disrupts plasma membrane a2d-1 expression by 86.2% compared to wt. It abolshes the ability of a2d-1 to promote Cav2.2 currents, it does not promote Cav2.2 cell surface exprtession or trafficking in hippocampal neurons and it shows reduced complex formation with Cav2.2 and limited proteolytic cleavage. Suggests the HA-a2b-1 with the G209D variant remians largely as the uncleaved imaature form, indicating that it probably remains in the endoplasmic reticulum - suggests LOF effect. Sources: NHS GMS; to: Dahimne et al, 2022, 35293990 - two unrelated patients with biallelic CACNA2D1 variants - trio exome sequencing - identified by gene matcher. Patient 1: homozygous fs variant c.818_821dup p.(Ser275fs) - healthy parents het carriers. Patient 2: compound het for a fs c.13_23dup p.(Leu9fs) and a missense variant c.626G>A p.(Gly209Asp) - parents healthy carriers of each of the variants. Both individuals show a highly consistent phenotype, corresponding to DEE - microcephalic, severe hypotonia, absent speech, spasticity, choreiform movements, orofacial dyskinesia and cortical visual impairement. Brain imaging showed corpus callosum hypoplasia and progressive volume loss in both. Both patients also showed insensitivity to pain. Looking at mRNA level in patient fibroblasts in both patients showed it was reduced to 6-9% compared to control fibroblasts. Also data suggest the fs variants result in LOF. Gly209 - this Gly is important for maintaining a 3-strand-beta-sheet-stability and simultaneously provididn ga critial turn in the structure and is absoloutely invariant in both CACNA2D1 and CACNA2D2 orthologs in all vertebrates and paralogs and predecessors from low invertebrates. Functional work on the missense change shows it disrupts plasma membrane a2d-1 expression by 86.2% compared to wt. It abolishes the ability of a2d-1 to promote Cav2.2 currents, it does not promote Cav2.2 cell surface expression or trafficking in hippocampal neurons and it shows reduced complex formation with Cav2.2 and limited proteolytic cleavage. Suggests the HA-a2b-1 with the G209D variant remains largely as the uncleaved imaature form, indicating that it probably remains in the endoplasmic reticulum - suggests LOF effect. Sources: NHS GMS |
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| Early onset or syndromic epilepsy v2.500 | CACNA2D1 |
Helen Lord gene: CACNA2D1 was added gene: CACNA2D1 was added to Genetic epilepsy syndromes. Sources: NHS GMS Mode of inheritance for gene: CACNA2D1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CACNA2D1 were set to 35293990 Phenotypes for gene: CACNA2D1 were set to Early onset developmental epilepsy Review for gene: CACNA2D1 was set to AMBER Added comment: Dahimne et al, 2022, 35293990 - two unrelated patients with biallelic CACNA2D1 variants - trio exome sequencing - identified by gene matcher. Patient 1: homozygous fs variant c.818_821dup p.(Ser275fs) - healthy parents het carriers. Patient 2: compound het for a fs c.13_23dup p.(Leu9fs) and a missense variant c.626G>A p.(Gly209Asp) - parents healthy carriers of each of the variants. Both individuals show a highly conssitent phenotype, corresponding to DEE - microcephalic, severe hypotonia, absent speech, spasticity, choreiform movements, orofacial dyskinesia and cortical visual impairement. Brain imaging showed corpus callosum hypoplasia and progressive volume loss in both. Both patients also showed insensitivty to apin Looking at mRNA level in patient fibroblasts in both pTIWNTS showed it was reduced to 6-9% compared to control fibroblasts. Also data suggest the fs variants result in LOF. Gly209 - this Gly is importnat for maintaining a 3-strand-beta-sheet-stability and simultaneously provididn ga critial turn in the structure and is absoloutely invariant in both CACNA2D1 and CACNA2D2 orthologs in all vertebrates and paralogs and predecessors from low invertebrates. Functional work on the missense change shows it disrupts plasma membrane a2d-1 expression by 86.2% compared to wt. It abolshes the ability of a2d-1 to promote Cav2.2 currents, it does not promote Cav2.2 cell surface exprtession or trafficking in hippocampal neurons and it shows reduced complex formation with Cav2.2 and limited proteolytic cleavage. Suggests the HA-a2b-1 with the G209D variant remians largely as the uncleaved imaature form, indicating that it probably remains in the endoplasmic reticulum - suggests LOF effect. Sources: NHS GMS |
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