ClinVar Genomic variation as it relates to human health

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.

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].

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)

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.

Variant summary: CPA6 c.799G>A (p.Gly267Arg) results in a non-conservative amino acid change located in the peptidase M14, carboxypeptidase A domain (IPR000834) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0029 in 1614204 control chromosomes, predominantly at a frequency of 0.0034 within the African or African-American subpopulation in the gnomAD database (v4.1.0), including 8 homozygotes. c.799G>A has been reported in the literature in heterozygous individuals affected with temporal lobe epilepsy (Salzmann_2012). It has also been reported to co-occur with another CPA6 missense variant, p.Gln207Glu, either in cis or phase unknown, in patients with CPA6-Related Disorders (e.g. Sapio_2012, Muona_2015, van Eyk_2021, Bobbili_2018, Allen_2016, Sanchis-Juan_2023, Coppola_2024). These report(s) 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. The most pronounced variant effect results in <10% of normal carboxypeptidase activity in transfected cells (Salzmann_2012, Sapio_2012). The following publications have been ascertained in the context of this evaluation (PMID: 26648591, 29358611, 38088023, 25401298, 21922598, 37541188, 23105115, 34531397). ClinVar contains an entry for this variant (Variation ID: 281269). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.

CAADphred>15

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.