ClinVar Miner

Submissions for variant NM_000097.7(CPOX):c.520G>A (p.Ala174Thr)

gnomAD frequency: 0.00016  dbSNP: rs199514514
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CeGaT Center for Human Genetics Tuebingen RCV001092356 SCV001248817 uncertain significance not provided 2019-07-01 criteria provided, single submitter clinical testing
Illumina Laboratory Services, Illumina RCV001150886 SCV001311981 benign Hereditary coproporphyria 2018-01-12 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Invitae RCV001092356 SCV001492926 uncertain significance not provided 2023-12-28 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 174 of the CPOX protein (p.Ala174Thr). This variant is present in population databases (rs199514514, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of acute hepatic porphyria (PMID: 30385147). ClinVar contains an entry for this variant (Variation ID: 872083). 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) performed at Invitae indicates that this missense variant is not expected to disrupt CPOX protein function with a negative predictive value of 80%. 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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