Submissions for variant NM_001122764.3(PPOX):c.767C>G (p.Pro256Arg)

gnomAD frequency: 0.00660  dbSNP: rs12735723

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000961007	SCV001108036	benign	not provided	2024-01-25	criteria provided, single submitter	clinical testing
Mendelics	RCV000986448	SCV001135454	uncertain significance	Variegate porphyria	2019-05-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000986448	SCV001255186	likely benign	Variegate porphyria	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Department of Medical Genomics, Royal Prince Alfred Hospital	RCV000986448	SCV002538984	benign	Variegate porphyria	2022-06-30	criteria provided, single submitter	curation	The PPOX:c.767C>G p.(Pro256Arg) variant has a gnomAD v2.1.1 FAF of 0.9288% (European non-Finnish). In a control population, allele frequency was 5%, with ~10% in the French cohort (Whatley et al 1999, PMID 10486317). In vitro functional studies found normal PPOX activity in transfected COS cells (Kauppinen et al 2001, PMID 11286631). in silico modelling predicts non-deleterious effect (REVEL score 0.495). Fulfils ACMG/AMP criteria BA1, BS3_supporting, BP4 and so is classified as Benign.
Genetics and Molecular Pathology, SA Pathology	RCV000986448	SCV002556729	benign	Variegate porphyria	2021-05-11	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000961007	SCV004009898	benign	not provided	2023-11-01	criteria provided, single submitter	clinical testing	PPOX: BP4, BS1, BS2
OMIM	RCV003324496	SCV000029459	pathogenic	Variegate porphyria, childhood-onset	2001-04-01	no assertion criteria provided	literature only
Reproductive Health Research and Development, BGI Genomics	RCV000986448	SCV001142311	benign	Variegate porphyria	2020-01-06	no assertion criteria provided	curation	NM_000309.3:c.767C>G in the PPOX gene has an allele frequency of 0.012 in European (Finnish) subpopulation in the gnomAD database, including eight homozygous occurrences. Functional studies indicated that this variant resulted in less than half of the normal PPOX activity in the prokaryotic expression system but the activity was almost normal in eukaryotic expression (PMID: 11286631). In addition, Whatley et al. reported this variant as a polymorphism (PMID: 10486317). Taken together, we interprete this variant as Benign/Likely benign variant. ACMG/AMP criteria applied: BS1; BS2; BS3.
Clinical Genetics, Academic Medical Center	RCV000961007	SCV001924864	likely benign	not provided		no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000961007	SCV001963218	likely benign	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003924820	SCV004746364	likely benign	PPOX-related disorder	2020-05-19	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).