ClinVar Genomic variation as it relates to human health

PP3, PP4, PM2, PS3, PS4_moderate

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 201 of the CPOX protein (p.Glu201Lys). This variant is present in population databases (no rsID available, gnomAD 0.004%). This missense change has been observed in individuals with autosomal dominant hereditary coproporphyria (PMID: 9298818, 11309681; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 845386). 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 expected to disrupt CPOX protein function. Experimental studies have shown that this missense change affects CPOX function (PMID: 11309681). For these reasons, this variant has been classified as Pathogenic.

Variant summary: CPOX c.601G>A (p.Glu201Lys) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251478 control chromosomes (gnomAD). c.601G>A has been reported in the literature in multiple heterozygous individuals affected with Hereditary Coproporphyria (Schreiber_1997, Lamoril_2001, Yasuda_2019), which is consistent with the disease possessing both autosomal dominant and autosomal recessive modes of inheritance for CPOX (MIM 121300). These data indicate that the variant is very likely to be associated with disease. When expressed in E. coli and assayed for activity, the variant recombinant protein had 1% residual activity compared to wild-type recombinant protein (Lamoril_2001). Two ClinVar submitters have assessed the variant since 2014: both classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

The CPOX c.601G>A (p.Glu201Lys) variant, also known as 301G>A (Glu101Lys), is reported in the literature in several individuals affected with autosomal dominant hereditary coproporphyria (Lamoril J et al., PMID: 11309681; Schreiber WE et al., PMID: 929881 Yasuda M et al., PMID: 30594473) and has been reported in the ClinVar database as a germline pathogenic variant by several submitters. The variant is only observed on 5/282,856 alleles in the general population (gnomAD v.2.1.1), indicating it is not a common variant. Computational predictors indicate that the variant is damaging, evidence that correlates with impact to coproporphyrinogen oxidase function. In support of this prediction, studies show reduced activity of the variant protein compared to wild type, indicating that this variant impacts protein function (Lamoril J et al., PMID: 11309681; Schmitt C et al., PMID: 16159891). Based on available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as likely pathogenic and may display reduced penetrance.