rs121917868

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PP3_StrongPP5_Very_Strong

The NM_000097.7(CPOX):c.1210A>G(p.Lys404Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000644 in 1,613,944 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000063 ( 0 hom. )

Consequence

CPOX
NM_000097.7 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 7.67

Publications

17 publications found

Variant links:

Genes affected

CPOX (HGNC:2321): (coproporphyrinogen oxidase) The protein encoded by this gene is the sixth enzyme of the heme biosynthetic pathway. The encoded enzyme is soluble and found in the intermembrane space of mitochondria. This enzyme catalyzes the stepwise oxidative decarboxylation of coproporphyrinogen III to protoporphyrinogen IX, a precursor of heme. Defects in this gene are a cause of hereditary coproporphyria (HCP).[provided by RefSeq, Oct 2009]

CPOX Gene-Disease associations (from GenCC):

CPOX-related hereditary coproporphyria
Inheritance: SD Classification: DEFINITIVE Submitted by: ClinGen
hereditary coproporphyria
Inheritance: AD, AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp
harderoporphyria
Inheritance: AR Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Genomics England PanelApp

CPOX links:

ENSG00000285635 (HGNC:):

ENSG00000285635 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.947

PP5

Variant 3-98581474-T-C is Pathogenic according to our data. Variant chr3-98581474-T-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 453.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
CPOX	NM_000097.7 link	c.1210A>G	p.Lys404Glu	missense_variant	Exon 6 of 7	ENST00000647941.2	NP_000088.3
CPOX	XM_005247125.5 link	c.1173-3204A>G		intron_variant	Intron 5 of 5		XP_005247182.1
CPOX	XR_001740025.3 link	n.1280-3204A>G		intron_variant	Intron 5 of 6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CPOX	ENST00000647941.2 link	c.1210A>G	p.Lys404Glu	missense_variant	Exon 6 of 7		NM_000097.7	ENSP00000497326.1
ENSG00000285635	ENST00000512905.6 link	n.94A>G		non_coding_transcript_exon_variant	Exon 2 of 4	5		ENSP00000425880.1
CPOX	ENST00000510489.1 link	n.460A>G		non_coding_transcript_exon_variant	Exon 2 of 2	2

Frequencies

GnomAD3 genomes

AF:

0.0000789

AC:

AN:

152160

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000398

AC:

AN:

251470

AF XY:

0.0000441

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000703

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000629

AC:

AN:

1461784

Hom.:

Cov.:

AF XY:

0.0000564

AC XY:

AN XY:

727190

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39692

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53410

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0000809

AC:

AN:

1111932

Other (OTH)

AF:

0.0000166

AC:

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.442

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000789

AC:

AN:

152160

Hom.:

Cov.:

AF XY:

0.0000673

AC XY:

AN XY:

74336

show subpopulations

African (AFR)

AF:

0.0000483

AC:

AN:

41440

American (AMR)

AF:

0.0000654

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5202

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10596

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000132

AC:

AN:

68024

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000224

Hom.:

Bravo

AF:

0.0000793

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000494

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000119

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Jun 26, 2017

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method: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. -

May 08, 2020

Revvity Omics, Revvity

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 07, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method: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. -

Harderoporphyria

Pathogenic:2

Jan 25, 2023

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method: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). -

Feb 15, 1998

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

CPOX-related hereditary coproporphyria

Pathogenic:1

Mar 10, 2022

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

Hereditary coproporphyria;C0342859:Harderoporphyria

Pathogenic:1

Jan 23, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.93

BayesDel_addAF

Pathogenic

0.37

BayesDel_noAF

Pathogenic

0.49

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.75

D;D

Eigen

Pathogenic

0.97

Eigen_PC

Pathogenic

0.90

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

D;.

M_CAP

Pathogenic

0.31

MetaRNN

Pathogenic

0.95

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.6

H;H

PhyloP100

7.7

PrimateAI

Uncertain

0.79

PROVEAN

Uncertain

-3.9

D;.

REVEL

Pathogenic

0.94

Sift

Benign

0.033

D;.

Sift4G

Benign

0.090

T;.

Polyphen

1.0

D;D

Vest4

0.96

MVP

0.98

MPC

1.7

ClinPred

0.95

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.92

gMVP

0.81

Mutation Taster

=25/75

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over