Submissions for variant NM_020361.5(CPA6):c.799G>A (p.Gly267Arg)

gnomAD frequency: 0.00239  dbSNP: rs61738009

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000711316	SCV000331966	uncertain significance	not provided	2018-05-25	criteria provided, single submitter	clinical testing
Claritas Genomics	RCV000449611	SCV000537841	uncertain significance	Global developmental delay	2017-02-21	criteria provided, single submitter	clinical testing
Invitae	RCV001082234	SCV000651985	likely benign	Febrile seizures, familial, 11	2023-11-15	criteria provided, single submitter	clinical testing
Athena Diagnostics Inc	RCV000711316	SCV000841657	uncertain significance	not provided	2018-09-06	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000023777	SCV001325623	uncertain significance	Familial temporal lobe epilepsy 5	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Baylor Genetics	RCV000023777	SCV001526814	uncertain significance	Familial temporal lobe epilepsy 5	2018-02-01	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
GeneDx	RCV000711316	SCV001792337	uncertain significance	not provided	2021-01-04	criteria provided, single submitter	clinical testing	Reported in two unrelated individuals with temporal lobe epilepsy who were not reported to harbor the Q207E variant and had no detectable mutant protein in the extracellular matrix where wild-type enzyme is typically observed (Salzmann et al., 2012); Reported in an individual with temporal lobe epilepsy who was also heterozygous for the Q207E variant, but familial segregation information was not included (Sapio et al., 2012; Salzmann et al., 2012); Reported in cis with Q207E in an individual with early onset epileptic encephalopathy, inherited from the individual's mother who was reported to have unexplained epilepsy but not epileptic encephalopathy (Allen et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23105115, 26648591, 32581362, 33096746, 28761347, 29358611, 21922598)
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000711316	SCV002011524	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
New York Genome Center	RCV002227465	SCV002506899	uncertain significance	Familial temporal lobe epilepsy 5; Febrile seizures, familial, 11	2021-06-21	criteria provided, single submitter	clinical testing	The inherited missense variant c.799G>A (p.Gly267Arg) in the CPA6 gene has been reported in the literature in individuals affected with epilepsy [PMIDs: 21922598, 23105115, 26648591]. This variant has been reported as heterozygous in two unrelated individuals affected with temporal lobe epilepsy [PMID:21922598]. The c.799G>A (p.Gly267Arg) variant has 0.002496 allele frequency in the gnomAD(v3) database (380 out of 152214 heterozygous alleles, no homozygotes). This variant affects evolutionarily conserved residues and is predicted deleterious by multiple in silico prediction tools. In vitro functional expression studies in cellular assays suggest that this variant reduces the CPA6 enzymatic activity compared to wild type protein [PMIDs: 21922598, 23105115]. However, additional studies are needed to determine the clinical significance of this variant. Based on the available evidence, the inherited heterozygous missense variant c.799G>A (p.Gly267Arg)] identified in the CPA6 gene is reported as a variant of uncertain significance.
Molecular Genetics Lab, CHRU Brest	RCV001082234	SCV004697787	likely benign	Febrile seizures, familial, 11		criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003930042	SCV004745029	uncertain significance	CPA6-related condition	2023-11-03	criteria provided, single submitter	clinical testing	The CPA6 c.799G>A variant is predicted to result in the amino acid substitution p.Gly267Arg. This variant is documented in the gnomAD general population database at a frequency inconsistent with autosomal dominant inheritance. However, it has been reported in the heterozygous state in 3 unrelated patients with temporal lobe epilepsy. One of the patients was heterozygous for a second variant of uncertain significance with unknown phase (Subject ET 158, p.Gln207Glu, Salzmann et al. 2012. PubMed ID: 21922598; Sapio et al. 2012. PubMed ID: 23105115). In another study, p.Gly267Arg and p.Gln207Glu were detected in cis, in a proband with developmental and epileptic encephalopathy who inherited the haplotype from his mother with unexplained epilepsy (Allen NM et al 2015. PubMed ID: 26648591). In vitro functional studies in an overexpression system have indicated that the p.Gly267Arg missense variant causes a strong reduction of protein level and carboxypeptidase activity, leading the authors to speculate that it may be pathogenic for recessive disease (Sapio et al. 2012. PubMed ID: 23105115). Taken together, due to conflicting genetic and functional evidence, the clinical significance of this variant is uncertain at this time.
OMIM	RCV000023777	SCV000045068	pathogenic	Familial temporal lobe epilepsy 5	2012-12-14	no assertion criteria provided	literature only
Bioinformatics Core, Luxembourg Center for Systems Biomedicine	RCV000656014	SCV000588290	pathogenic	Childhood epilepsy with centrotemporal spikes	2017-01-01	no assertion criteria provided	case-control	CAADphred>15
NIHR Bioresource Rare Diseases, University of Cambridge	RCV001003969	SCV001161978	likely pathogenic	Seizure; Focal-onset seizure; Irregular menstruation; Confusion; Palpitations; Periventricular heterotopia; Abnormal emotion		no assertion criteria provided	research