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Early onset or syndromic epilepsy v4.110 CPA6 Arina Puzriakova Tag for-review was removed from gene: CPA6.
Tag Q2_23_demote_red was removed from gene: CPA6.
Tag Q2_23_NHS_review was removed from gene: CPA6.
Tag Q2_23_expert_review was removed from gene: CPA6.
Tag refuted tag was added to gene: CPA6.
Early onset or syndromic epilepsy v4.110 CPA6 Arina Puzriakova reviewed gene: CPA6: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Early onset or syndromic epilepsy v4.109 CPA6 Arina Puzriakova Source Expert Review Red was added to CPA6.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Early onset or syndromic epilepsy v4.62 CPA6 John Taylor changed review comment from: The pathology of this gene is predicated on two publications: Salzmann et al. (2012) PubMed: 21922598 and Sapio et al. (2012) PubMed: 23105115. Both of these publications were issued prior to large population-based allele assessments and the evidence for pathogenicity is reliant on circumstantial evidence. None of the variants that form the foundation of this disease link would have sufficient evidence in support pathogenicity using current classification criteria. This gene should be recategorized as having a Red rating.

Evidence against pathogenicity for the reported variants:
Salzmann et al. (2012) proposed haploinsufficiency rather than gain of function; however, there is no obvious constraint score across the length of the gene. Previously reported pathogenic variants are, in some cases (see below), present in gnomAD at allele frequencies contrary to the incidence of the associated condition.

CPA6 p.(Ala270Val) rs114402678 has been reported has a homozygous variant in gnomADv3.1.2 in the non-neuro sub category (only samples that were not collected as part of a neurologic or psychiatric case/control study, or samples collected as part of a neurologic or psychiatric case/control study but designated as controls). The allele frequency and the observed number of homozygotes is not significantly different from the number of expected homozygote alleles based on the Hardy-Weinberg equilibrium.

CPA6(NM_020361.5):c.799G>A p.(Gly267Arg) rs61738009 was reported as a heterozygous pathogenic variant; however, this variant has been reported in >860 heterozygous individuals in gnomADv2.1.1 and v3.1.2.; to: The pathology of this gene is predicated on two publications: Salzmann et al. (2012) PubMed: 21922598 and Sapio et al. (2012) PubMed: 23105115. Both of these publications were issued prior to large population-based allele assessments and the evidence for pathogenicity is reliant on circumstantial evidence. None of the variants that form the foundation of this disease link would have sufficient evidence in support pathogenicity using current classification criteria. This gene should be recategorized as having a Red rating.

Evidence against pathogenicity for the reported variants:
Salzmann et al. (2012) proposed haploinsufficiency rather than gain of function; however, there is no obvious constraint score across the length of the gene. Previously reported pathogenic variants are, in some cases (see below), present in gnomAD at allele frequencies contrary to the incidence of the associated condition.

CPA6 p.(Ala270Val) rs114402678 has been reported has a homozygous variant in gnomADv3.1.2 in the non-neuro sub category (only samples that were not collected as part of a neurologic or psychiatric case/control study, or samples collected as part of a neurologic or psychiatric case/control study but designated as controls). The allele frequency and the observed number of homozygotes is not significantly different from the number of expected homozygote alleles based on the Hardy-Weinberg equilibrium.

CPA6(NM_020361.5):c.799G>A p.(Gly267Arg) rs61738009 was reported as a heterozygous pathogenic variant; however, this variant has been reported in >860 heterozygous individuals in gnomADv2.1.1 and v3.1.2.
Early onset or syndromic epilepsy v4.62 CPA6 John Taylor reviewed gene: CPA6: Rating: RED; Mode of pathogenicity: Other; Publications: PMID:21922598, 23105115; Phenotypes: ; Mode of inheritance: Other
Early onset or syndromic epilepsy v4.39 CPA6 Eleanor Williams commented on gene: CPA6
Early onset or syndromic epilepsy v4.39 CPA6 Eleanor Williams Tag Q2_23_NHS_review tag was added to gene: CPA6.
Tag Q2_23_expert_review tag was added to gene: CPA6.
Early onset or syndromic epilepsy v4.39 CPA6 Eleanor Williams Tag to_be_confirmed_NHSE was removed from gene: CPA6.
Tag Q2_23_demote_red tag was added to gene: CPA6.
Early onset or syndromic epilepsy v4.37 CPA6 Ian Berry reviewed gene: CPA6: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.498 CPA6 Sarah Leigh commented on gene: CPA6: The to_be_confirmed_NHSE tag has been added, as further NHSE review is required.
Early onset or syndromic epilepsy v2.491 CPA6 Sarah Leigh Tag to_be_confirmed_NHSE tag was added to gene: CPA6.
Early onset or syndromic epilepsy v2.277 CPA6 Sarah Leigh Tag for-review tag was added to gene: CPA6.
Early onset or syndromic epilepsy v2.277 CPA6 Sarah Leigh commented on gene: CPA6: After consultation Helen Lord, recommend change of MOI to BIALLELIC, autosomal or pseudosomal
Early onset or syndromic epilepsy v2.277 CPA6 Sarah Leigh edited their review of gene: CPA6: Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.277 CPA6 Helen Lord reviewed gene: CPA6: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Early onset or syndromic epilepsy v2.250 CPA6 Zornitza Stark reviewed gene: CPA6: Rating: AMBER; Mode of pathogenicity: None; Publications: 25875328, 21922598, 23105115; Phenotypes: Epilepsy, familial temporal lobe, 5 MIM#614417, Febrile seizures, familial, 11 MIM#614418; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.191 CPA6 Rebecca Foulger Source Wessex and West Midlands GLH was added to CPA6.
Early onset or syndromic epilepsy v1.190 CPA6 Rebecca Foulger Source NHS GMS was added to CPA6.
Early onset or syndromic epilepsy v1.189 CPA6 Rebecca Foulger edited their review of gene: CPA6: 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: John Taylor and Helen Lord. Suggested gene rating: Green. ; Changed rating: AMBER
Early onset or syndromic epilepsy v1.188 CPA6 Tracy Lester reviewed gene: CPA6: Rating: GREEN; Mode of pathogenicity: ; Publications: 23105115, 21922598 ; Phenotypes: Epilepsy, familial temporal lobe, 5,614417, Febrile seizures, familial, 11,614418; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early onset or syndromic epilepsy CPA6 Sarah Leigh reviewed CPA6
Early onset or syndromic epilepsy CPA6 Sarah Leigh classified CPA6 as Green List (high evidence)
Early onset or syndromic epilepsy CPA6 Sarah Leigh Added gene to panel