ClinVar Miner

Submissions for variant NM_020361.5(CPA6):c.1271C>T (p.Ala424Val)

gnomAD frequency: 0.00024  dbSNP: rs72654981
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000526086 SCV000651979 uncertain significance Febrile seizures, familial, 11 2022-12-06 criteria provided, single submitter clinical testing This variant has not been reported in the literature in individuals affected with CPA6-related conditions. This variant is present in population databases (rs72654981, gnomAD 0.05%), and has an allele count higher than expected for a pathogenic variant. This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 424 of the CPA6 protein (p.Ala424Val). ClinVar contains an entry for this variant (Variation ID: 472761). 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. Experimental studies have shown that this missense change affects CPA6 function (PMID: 23105115). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on CPA6 protein function.
Illumina Laboratory Services, Illumina RCV001160187 SCV001321967 uncertain significance Familial temporal lobe epilepsy 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.
Fulgent Genetics, Fulgent Genetics RCV002483479 SCV002790741 uncertain significance Familial temporal lobe epilepsy 5; Febrile seizures, familial, 11 2022-01-13 criteria provided, single submitter clinical testing

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