NM_000097.7(CPOX):c.995G>A (p.Arg332Gln) AND not provided

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: Aug 1, 2024
Review status:: criteria provided, conflicting classifications

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000522440.11

Allele description [Variation Report for NM_000097.7(CPOX):c.995G>A (p.Arg332Gln)]

NM_000097.7(CPOX):c.995G>A (p.Arg332Gln)

Gene:

CPOX:coproporphyrinogen oxidase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

3q11.2

Genomic location:

Preferred name:

NM_000097.7(CPOX):c.995G>A (p.Arg332Gln)

HGVS:

NC_000003.12:g.98585618C>T
NG_015994.2:g.12994G>A
NM_000097.7:c.995G>AMANE SELECT
NP_000088.3:p.Arg332Gln
LRG_1077t1:c.995G>A
LRG_1077:g.12994G>A
LRG_1077p1:p.Arg332Gln
NC_000003.11:g.98304462C>T
NM_000097.5:c.995G>A

Protein change:

R332Q

Links:

dbSNP: rs781627991

NCBI 1000 Genomes Browser:

rs781627991

Molecular consequence:

NM_000097.7:c.995G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000617838	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Uncertain significance (Sep 14, 2017)	germline	clinical testing	Citation Link,
SCV000963765	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 31, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 18557518, 23582006, 28492532
SCV005330415	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Uncertain significance (Aug 1, 2024)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000617838

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification (06012015))

Uncertain significance
(Sep 14, 2017)

germline

clinical testing

Citation Link,

SCV000963765

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Dec 31, 2023)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV005330415

CeGaT Center for Human Genetics Tuebingen

criteria provided, single submitter

(CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)

Uncertain significance
(Aug 1, 2024)

germline

clinical testing

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Hereditary coproporphyria: report of an Irish kindred and identification of a novel gene mutation.

Gorman CS, Gill D, Darby C, Crowley V, Mahony MJ.

Ir Med J. 2008 Apr;101(4):125. No abstract available.

PubMed [citation]

PMID:: 18557518

Co-existence of hereditary coproporphyria and porphyria cutanea tarda: The importance of genetic testing.

Rudd A, Grant J, Varigos G, Morgan V, Winship I.

Australas J Dermatol. 2013 May;54(2):e50-2. doi: 10.1111/j.1440-0960.2011.00875.x. Epub 2012 Mar 21.

PubMed [citation]

PMID:: 23582006

See all PubMed Citations (3)

Details of each submission

From GeneDx, SCV000617838.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

The R332Q variant was identified in two unrelated families with clinical and biochemical features suggestive of hereditary coproporphyria (HCP) (Gorman et al., 2008; Ma et al., 2011). In both families, the R332Q variant was identified in several individuals with acute episodes of porphyria symptoms, some of whom responded to treatment with heme arginate infusions, and was also detected in unaffected family members (Gorman et al., 2008; Ma et al., 2011; Rudd et al., 2013). The R332Q variant is not observed at significance frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). It is a semi-conservative amino acid substitution that occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000963765.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 332 of the CPOX protein (p.Arg332Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with coproporphyria (PMID: 18557518, 23582006; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 449558). 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%. For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From CeGaT Center for Human Genetics Tuebingen, SCV005330415.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	not provided

Description

CPOX: PM5, PP3

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

Last Updated: Oct 20, 2024

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