ClinVar Miner

Submissions for variant NM_020361.5(CPA6):c.581G>A (p.Gly194Asp) (rs201589247)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000279381 SCV000340116 uncertain significance not provided 2016-03-24 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001163865 SCV001325948 uncertain significance Epilepsy, familial temporal lobe, 5 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Invitae RCV001214811 SCV001386516 uncertain significance Febrile seizures, familial, 11 2019-08-15 criteria provided, single submitter clinical testing This sequence change replaces glycine with aspartic acid at codon 194 of the CPA6 protein (p.Gly194Asp). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and aspartic acid. This variant is present in population databases (rs201589247, ExAC 0.02%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has not been reported in the literature in individuals with CPA6-related conditions. ClinVar contains an entry for this variant (Variation ID: 286614). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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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