Submissions for variant NM_020361.5(CPA6):c.707C>T (p.Pro236Leu) (rs201552815)

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Total submissions: 2

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000483962	SCV000573366	uncertain significance	not provided	2017-02-27	criteria provided, single submitter	clinical testing	The P236L variant in the CPA6 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The P236L variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The P236L variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret P236L as a variant of uncertain significance.
Invitae	RCV000692380	SCV000820200	uncertain significance	Febrile seizures, familial, 11	2018-02-26	criteria provided, single submitter	clinical testing	This sequence change replaces proline with leucine at codon 236 of the CPA6 protein (p.Pro236Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs201552815, ExAC 0.009%). This variant has not been reported in the literature in individuals with CPA6-related disease. ClinVar contains an entry for this variant (Variation ID: 423645). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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