Submissions for variant NM_020361.5(CPA6):c.619C>G (p.Gln207Glu)

gnomAD frequency: 0.00121  dbSNP: rs35993949

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Claritas Genomics	RCV000449549	SCV000537840	uncertain significance	Global developmental delay	2017-02-21	criteria provided, single submitter	clinical testing
GeneDx	RCV000711314	SCV000581747	uncertain significance	not provided	2021-01-04	criteria provided, single submitter	clinical testing	Reported in cis with G267R 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) Reported in an individual with temporal lobe epilepsy who was also heterozygous for the G267R variant, but familial segregation information was not included (Sapio et al., 2012) 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: 32581362, 29358611, 23105115, 26648591)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001085402	SCV000651981	likely benign	Febrile seizures, familial, 11	2023-10-13	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000711314	SCV000708910	uncertain significance	not provided	2018-05-25	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000711314	SCV000841655	uncertain significance	not provided	2018-09-06	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000445558	SCV001325947	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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Baylor Genetics	RCV000445558	SCV001526813	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].
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000711314	SCV002011525	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
New York Genome Center	RCV002227475	SCV002506900	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.619C>G (p.Gln207Glu) in the CPA6 gene has been reported in the literature in individuals affected with epilepsy [PMIDs: 21922598, 23105115, 26648591]. The variant has 0.001222 allele frequency in the gnomAD(v3) database (186 out of 152174 heterozygous alleles, no homozygotes). It affects evolutionarily conserved residues and is predicted deleterious by multiple in silico prediction tools. In vitro functional expression studies in cellular assays suggest that the 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 variants [c.619C>G(p.Gln207Glu)identified in the CPA6 gene is reported as a variant of uncertain significance.
Molecular Genetics Lab, CHRU Brest	RCV001085402	SCV004697786	likely benign	Febrile seizures, familial, 11		criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004767260	SCV005380992	uncertain significance	not specified	2024-08-15	criteria provided, single submitter	clinical testing	Variant summary: CPA6 c.619C>G (p.Gln207Glu) results in a conservative amino acid change located in the Peptidase M14, carboxypeptidase A domain (IPR000834) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.002 in 1611506 control chromosomes in the gnomAD database, including 4 homozygotes, suggesting the variant could be benign. c.619C>G has been reported in the literature in individuals of heterozygous or unspecified genotype affected with neurodevelopmental disorders including focal or progressive myoclonic epilepsy, early onset epileptic encephalopathy, intellectual disability, cerebral palsy, or other unspecified neurodevelopmental disorder all without evidence of causality, often found in cis or unknown phase with c.799G>A, p.G267R (e.g. Sapio_2012, Muona_2014, Allen_2015, Moortgat_2018, vanEyk_2021, Sanchis-Juan_2023, Coppola_2023). These reports do not provide unequivocal conclusions about association of the variant with CPA6-Related Disorders. At least one publication reports experimental evidence evaluating an impact on protein function showing severely reduced CPA6 activity and protein expression in vitro (e.g. Sapio_2012). The following publications have been ascertained in the context of this evaluation (PMID: 26648591, 38088023, 29180823, 25401298, 37541188, 23105115, 34531397). ClinVar contains an entry for this variant (Variation ID: 393467). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
OMIM	RCV000445558	SCV000537137	pathogenic	Familial temporal lobe epilepsy 5	2012-12-14	no assertion criteria provided	literature only
Bioinformatics Core, Luxembourg Center for Systems Biomedicine	RCV000656015	SCV000588291	pathogenic	Childhood epilepsy with centrotemporal spikes	2017-01-01	no assertion criteria provided	case-control	CAADphred>15
NIHR Bioresource Rare Diseases, University of Cambridge	RCV001003970	SCV001161979	likely pathogenic	Seizure; Focal-onset seizure; Irregular menstruation; Confusion; Palpitations; Periventricular heterotopia; Abnormal emotional state		no assertion criteria provided	research