Submissions for variant NM_000250.2(MPO):c.1705C>T (p.Arg569Trp)

gnomAD frequency: 0.00173  dbSNP: rs119468010

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000366635	SCV000329997	pathogenic	not provided	2024-04-04	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: apopro-MPO does not undergo post-translational processing to enzymatically active MPO resulting in absent MPO activity (PMID: 8621627, 32758447); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 9354683, 9468285, 34662886, 7904599, 15108282, 8142659, 17384005, 24385801, 32758448, 34426522, 31589614, 32531373, 32758447, 35761024, 8621627)
CeGaT Center for Human Genetics Tuebingen	RCV000366635	SCV001247509	pathogenic	not provided	2021-01-01	criteria provided, single submitter	clinical testing
Genetic Diagnostics Department, Viafet Genomics Laboratory	RCV000003810	SCV001976439	pathogenic	Myeloperoxidase deficiency	2021-08-23	criteria provided, single submitter	clinical testing	As part of Carrier Screening testing performed at Viafet Genomics Laboratory, this variant was identified in a heterozygous state in a patient who is not affected with this condition. This variant has been identified in a homozygous and compound heterozygous state in patients affected with Myeloperoxidase Deficiency (PMIDs: 7904599, 8142659 and 9468285).
Revvity Omics, Revvity	RCV000003810	SCV002023512	likely pathogenic	Myeloperoxidase deficiency	2021-12-26	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000366635	SCV002103266	pathogenic	not provided	2021-05-20	criteria provided, single submitter	clinical testing	PM3_very strong, PS3, PS4_moderate, PP3
AiLife Diagnostics, AiLife Diagnostics	RCV000366635	SCV002502200	likely pathogenic	not provided	2022-03-08	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002490304	SCV002780401	pathogenic	Myeloperoxidase deficiency; Alzheimer disease type 1	2022-04-11	criteria provided, single submitter	clinical testing
OMIM	RCV000003810	SCV000023975	pathogenic	Myeloperoxidase deficiency	2004-05-01	no assertion criteria provided	literature only
GenomeConnect, ClinGen	RCV000003810	SCV000607006	not provided	Myeloperoxidase deficiency		no assertion provided	phenotyping only	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000366635	SCV001551737	likely pathogenic	not provided		no assertion criteria provided	clinical testing	The MPO p.R569W variant was identified in the literature in five families with by hereditary myeloperoxidase deficiency in the heterozygous, homozygous and presumed compound heterozygous state. All individuals with p.R569W exhibited abnormal MPO activity, with one homozygous individual being completely MPO deficient while heterozygotes were partially to completely MPO deficient (Nauseef_1998_PMID:9468285). Furthermore, in a cohort of 6 patients with MPO deficiency, one patient was identified to be a compound heterozygote for p.R569W and p.M251T but also had an additional variant in JAK2 (Alexandre_2016_PMID_27013444). The p.R569W variant was identified in dbSNP (ID: rs119468010) and ClinVar (classified as pathogenic by GeneDx). The variant was identified in control databases in 416 of 282876 chromosomes at a frequency of 0.001471 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 370 of 129182 chromosomes (freq: 0.002864), Other in 7 of 7226 chromosomes (freq: 0.000969), European (Finnish) in 13 of 25122 chromosomes (freq: 0.000518), Latino in 14 of 35440 chromosomes (freq: 0.000395), African in 8 of 24968 chromosomes (freq: 0.00032) and South Asian in 4 of 30616 chromosomes (freq: 0.000131), but was not observed in the Ashkenazi Jewish or East Asian populations. The p.R569 residue is conserved in mammals but not in more distantly related organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. Functional studies indicate protein function is affected as a result of this variant, as p.R569W cell lines had a defective maturation process, exhibited no MPO activity compared to wild type cells, failed to incorporate heme, exit the ER, or undergo proteolytic processing to mature MPO subunits and had prolonged association with calnexin and calreticulin compared to complexes with wild type MPO (Sawayama_2008_PMID:18273043; Nauseef_1996_PMID:8621627; Nauseef_1997_PMID:9507022). In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more pathogenic role for this variant. This variant is classified as likely pathogenic.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000366635	SCV001744111	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000366635	SCV001952510	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000366635	SCV001966910	pathogenic	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003415644	SCV004109188	likely pathogenic	MPO-related disorder	2024-04-05	no assertion criteria provided	clinical testing	The MPO c.1705C>T variant is predicted to result in the amino acid substitution p.Arg569Trp. This variant has been reported in the homozygous and compound heterozygous state in multiple individuals with myeloperoxidase deficiency (Nauseef et al. 1994. PubMed ID: 7904599; Marchetti et al. 2004. PubMed ID: 15108282; Vergnano et al. 2020. PubMed ID: 32758448). This variant is reported in 0.29% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as likely pathogenic.
Undiagnosed Diseases Network, NIH	RCV000003810	SCV004242198	pathogenic	Myeloperoxidase deficiency	2023-05-22	no assertion criteria provided	clinical testing