ClinVar Miner

Submissions for variant NM_000097.7(CPOX):c.1339C>T (p.Arg447Cys)

gnomAD frequency: 0.00025  dbSNP: rs28931603
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Baylor Genetics RCV000415159 SCV000328791 uncertain significance Hereditary coproporphyria criteria provided, single submitter clinical testing
Invitae RCV001046689 SCV001210603 uncertain significance not provided 2024-01-06 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 447 of the CPOX protein (p.Arg447Cys). This variant is present in population databases (rs28931603, gnomAD 0.1%). This missense change has been observed in individual(s) with clinical features of coproporphyria (PMID: 11309681, 12181641, 27959697, 33763395). ClinVar contains an entry for this variant (Variation ID: 459). 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%. Experimental studies have shown that this missense change affects CPOX function (PMID: 11309681). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.
Genetics and Molecular Pathology, SA Pathology RCV000415159 SCV002761901 uncertain significance Hereditary coproporphyria 2021-10-11 criteria provided, single submitter clinical testing
GeneDx RCV001046689 SCV004034761 likely pathogenic not provided 2023-03-07 criteria provided, single submitter clinical testing Reported with a second CPOX variant on the same allele (in cis) in affected individuals from three families with hereditary coproporphyria, as well as without a second CPOX variant in an unaffected individual from one of these families (Wiman et al., 2002); Published functional studies demonstrate significantly reduced CPOX enzyme activity (Lamoril et al., 2001); 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: 11309681, 27959697, 34426522, 31589614, 33763395, 12181641)
Mayo Clinic Laboratories, Mayo Clinic RCV001046689 SCV004226139 uncertain significance not provided 2022-02-24 criteria provided, single submitter clinical testing PP3, PS3
OMIM RCV000000488 SCV000020637 pathogenic Coproporphyria 2002-01-01 no assertion criteria provided literature only

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