Research panel - Severe Paediatric Disorders
Gene: CPA6

CPA6 (carboxypeptidase A6)
EnsemblGeneIds (GRCh38): ENSG00000165078
EnsemblGeneIds (GRCh37): ENSG00000165078
OMIM: 609562, Gene2Phenotype
CPA6 is in 2 panels

3 reviews

Sarah Leigh (Genomics England Curator)

Red List (low evidence)

ClinGen has refuted the association between biallelic CPA6 variants and epilepsy and had disputed the association between monoallelic CPA6 variants and epilepsy (https://search.clinicalgenome.org/kb/gene-validity?page=1&size=25&search=CPA6)
Created: 28 Nov 2023, 1:53 p.m. | Last Modified: 28 Nov 2023, 1:53 p.m.

Panel Version: 1.176

Created: 28 Nov 2023, 1:53 p.m.
Last Modified: 28 Nov 2023, 1:53 p.m.
Panel version: 1.176

Ian Berry (Leeds Genetics Laboratory)

Red List (low evidence)

This gene should be retracted from the green list for all panels.
It is regarded as "disputed" and "refuted" evidence respectively by ClinGen curation.
The evidence supporting the association is largely based on observation of three variants which are common in the general population in studies by Salzmann et al 2012 & Sapio et al 2012.

https://www.deciphergenomics.org/sequence-variant/8-67483797-G-A/annotation/maf/both - this variant p.Ala270Val was seen in homozygosity in a small family but is also common in gnomAD with 2x homozygotes. It has not been replicated and is now considered benign/LB.

p.Gly267Arg and p.Gln207Glu were both observed in a single case by Sapio et al 2012, but these co-segregate extensively in gnomAD (approx. 1 in 160 European individuals has these variants, likely on the same haplotype) and no parental testing was done to determine phase. Both variants are likely to be benign.

There are no large cohort studies, functional evidence or other collaborating studies other than single observations since these two papers. The gene is not a particularly compelling candidate for epilepsy mechanistically and the animal model isn't convincing. This should not be green in my opinion and should be removed from this panel.
Created: 16 May 2023, 2:53 p.m. | Last Modified: 16 May 2023, 2:53 p.m.

Panel Version: 1.153

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Created: 16 May 2023, 2:53 p.m.
Last Modified: 16 May 2023, 2:53 p.m.
Panel version: 1.153

Louise Daugherty (Genomics England Curator)

I don't know

Initial gene list (NGC_genelist-20190823_GREEN_dis_moi_forCuration_20200211.xlsx) collated by Dr Courtney French (University of Cambridge University Hospital NHS Foundation), Dr Karyn Megy (Clinical Feedback Lead, NIHR BioResource - Rare Diseases Study, University of Cambridge University Hospital NHS Foundation), Dr Alba Sanchis-Juan (NIHR BioResource - Rare Diseases Study, University of Cambridge University Hospital NHS Foundation) and Lucy Raymond (Professor of Medical Genetics and Neurodevelopment, University of Cambridge University Hospital NHS Foundation). Submitted to the PanelApp resource January 2020 on behalf of the Next Generation Children Project, Addenbrookes' Hospital, Cambridge. Gene Symbol submitted: CPA6; Recommended initial gene rating: Green List (high evidence); Phenotypes: Epilepsy, familial temporal lobe, 5, 614417 (3) | Febrile seizures, familial, 11, 614418 (3); Mode of inheritance: Autosomal recessive, Autosomal dominant | Autosomal recessive
Created: 20 Feb 2020, 5:17 p.m. | Last Modified: 20 Feb 2020, 5:17 p.m.

Panel Version: 0.12

Created: 20 Feb 2020, 5:17 p.m.
Last Modified: 20 Feb 2020, 5:17 p.m.
Panel version: 0.12

Details

Mode of Inheritance

BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Sources

Expert Review Red
Next Generation Children Project
Expert list

Phenotypes

Epilepsy, familial temporal lobe, 5, 614417
Febrile seizures, familial, 11, 614418

OMIM

609562

Clinvar variants

Variants in CPA6

Penetrance

None

Publications

30847515

Panels with this gene

History Filter Activity

28 Nov 2023, Gel status: 1

Entity classified by Genomics England curator

Sarah Leigh (Genomics England Curator)

Gene: cpa6 has been classified as Red List (Low Evidence).

21 Feb 2020, Gel status: 3