Submissions for variant NM_000097.7(CPOX):c.1210A>G (p.Lys404Glu)

gnomAD frequency: 0.00009  dbSNP: rs121917868

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000498398	SCV000589679	likely pathogenic	not provided	2017-06-26	criteria provided, single submitter	clinical testing	The K404E variant in the CPOX gene has been reported previously along with another variant in an individual with harderoporphyria with severe hemolytic anemia with splenomegaly and compensatory hyperactive bone marrow. Carrier parents and sister were clinically unaffected but showed a decrease in CPOX activity (Lamoril et al., 1998). The K404E variant, also referred to as K304E using alternate nomenclature, was also reported in three siblings with harderoporphyria. The variant was assumed to be homozygous due to absence of the normal allele and decreased CPOX enzyme activity in the affected siblings, and the heterozygous state of the father along with parental enzyme studies demonstrating heterozygosity for the same enzymatic defect in both parents. DNA was not obtained from the mother (Lamoril et al., 1995). In functional studies, the K404E mutant enzyme exhibits reduced enzyme activity compared to wild type enzyme (Kim et al., 2013; Lamoril et al., 1995). The K404E variant is observed in 4/66724 (0.006%) alleles in the ExAC dataset, and no homozygous individuals were reported (Lek et al., 2016). The K404E variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. We interpret K404E as a likely pathogenic variant.
Invitae	RCV000498398	SCV001581532	pathogenic	not provided	2024-01-07	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 404 of the CPOX protein (p.Lys404Glu). This variant is present in population databases (rs121917868, gnomAD 0.009%). This missense change has been observed in individual(s) with harderoporphyria (PMID: 7757079, 9454777, 16159891). It has also been observed to segregate with disease in related individuals. This variant is also known as K304E. ClinVar contains an entry for this variant (Variation ID: 453). 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 with a positive predictive value of 80%. Experimental studies have shown that this missense change affects CPOX function (PMID: 16159891, 24078084). For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity	RCV000498398	SCV002023380	likely pathogenic	not provided	2020-05-08	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002496220	SCV002775074	likely pathogenic	Hereditary coproporphyria; Harderoporphyria	2022-01-23	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000000482	SCV003761251	likely pathogenic	Harderoporphyria	2023-01-25	criteria provided, single submitter	curation	The heterozygous p.Lys404Glu variant in CPOX was identified by our study in one individual with harderoporphyria. The p.Lys404Glu variant in CPOX has been previously reported in three unrelated individuals with harderoporphyria (PMID: 16159891, PMID: 9454777, PMID: 7757079) and segregated with disease in three affected individuals from one family (PMID: 7757079), but has been identified in 0.008% (2/24962) of African/African American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs121917868). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID: 453) and was interpreted as pathogenic by Invitae and OMIM and as likely pathogenic by GeneDx and PerkinElmer Genomics. Of the three affected individuals previously reported (PMID: 16159891, PMID: 9454777, PMID: 7757079), two were homozygotes (PMID: 16159891, PMID: 7757079) and one was a compound heterozygote who carried a variant of uncertain significance in trans (PMID: 9454777, ClinVar Variation ID: 457), which increases the likelihood that the p.Lys404Glu variant is pathogenic. In vitro functional studies provide some evidence that the p.Lys404Glu variant may slightly impact protein function (PMID: 24078084, PMID: 16159891, PMID: 7757079). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive harderoporphyria. ACMG/AMP Criteria applied: PM3, PM2_Supporting, PS3_Supporting, PP1, PP3 (Richards 2015).
OMIM	RCV000000482	SCV000020631	pathogenic	Harderoporphyria	1998-02-15	no assertion criteria provided	literature only