Submissions for variant NM_000250.2(MPO):c.2031-2A>C

gnomAD frequency: 0.00472  dbSNP: rs35897051

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000003816	SCV000221199	pathogenic	Myeloperoxidase deficiency	2014-09-26	criteria provided, single submitter	clinical testing	The 2031-2A>C variant in MPO has been previously identified in 1 compound heterozygous and 2 homozygous individuals with myeloperoxidase deficiency (Marchetti 2004). This variant is located in the 3' splice region and functional studies indicate that this variant leads to altered splicing (Marchetti 2004). In summary, the 2031-2A>C variant meets our criteria to be considered causative for myeloperoxidase deficiency (MPOD) in a recessive manner. However, the clinical relevance of MPOD is not well-established.
GeneDx	RCV000265536	SCV000329427	pathogenic	not provided	2022-11-27	criteria provided, single submitter	clinical testing	Reported as a heterozygous germline variant in multiple individuals with myeloid neoplasms (Kongkiatkamon et al., 2022); Splice site variant that destroys the canonical splice acceptor site in intron 11, and causes the activation of a cryptic splice site located 109 nucleotides upstream of the authentic splice site (Marchetti et al., 2004); This variant is associated with the following publications: (PMID: 20974672, 25714468, 34662886, 35026467, 24385801, 17384005, 15108282, 26764160, 26822949, 27301573, 27827828, 30487145, 31980526, 32758448, 34426522, 32758447, 32531373, 35761024)
CeGaT Center for Human Genetics Tuebingen	RCV000265536	SCV001334657	likely pathogenic	not provided	2024-01-01	criteria provided, single submitter	clinical testing	MPO: PM3, PS3:Moderate, PM2:Supporting, PP3
Institute of Human Genetics, University of Leipzig Medical Center	RCV000003816	SCV001439966	likely pathogenic	Myeloperoxidase deficiency	2019-01-01	criteria provided, single submitter	clinical testing	This variant was identified as compound heterozygous.
Knight Diagnostic Laboratories, Oregon Health and Sciences University	RCV000003816	SCV001448821	likely pathogenic	Myeloperoxidase deficiency	2019-07-08	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000265536	SCV002009349	pathogenic	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000003816	SCV002023510	likely pathogenic	Myeloperoxidase deficiency	2023-11-02	criteria provided, single submitter	clinical testing
AiLife Diagnostics, AiLife Diagnostics	RCV000265536	SCV002502221	likely pathogenic	not provided	2022-03-30	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002482823	SCV002778311	pathogenic	Myeloperoxidase deficiency; Alzheimer disease type 1	2022-04-12	criteria provided, single submitter	clinical testing
Payam Genetics Center, General Welfare Department of North Khorasan Province	RCV000003816	SCV003924023	pathogenic	Myeloperoxidase deficiency	2023-03-01	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003398437	SCV004104737	pathogenic	MPO-related condition	2024-02-26	criteria provided, single submitter	clinical testing	The MPO c.2031-2A>C variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. This variant has been reported to be causative for autosomal recessive myeloperoxidase deficiency (Marchetti et al. 2004. PubMed ID: 15108282; Vergnano et al. 2020. PubMed ID: 32758448). This variant is reported in 1.3% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. Variants that disrupt the consensus splice acceptor site in MPO are expected to be pathogenic, and this variant has been classified as pathogenic or likely pathogenic by multiple independent submitters to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/3632). This variant is interpreted as pathogenic.
OMIM	RCV000003816	SCV000023981	pathogenic	Myeloperoxidase deficiency	2004-05-01	no assertion criteria provided	literature only
GenomeConnect, ClinGen	RCV000003816	SCV000607007	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.
Reproductive Health Research and Development, BGI Genomics	RCV000003816	SCV001142475	pathogenic	Myeloperoxidase deficiency	2020-01-06	no assertion criteria provided	curation	NG_009629.1(NM_000250.1):c.2031-2A>C in the MPO gene has an allele frequency of 0.013 in Ashkenazi Jewish subpopulation in the gnomAD database. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. It was detected in individual with autosomal recessive Myeloperoxidase deficiency, compound heterozygous with c.1566_1579del14 (PMID:15108282). The patient's phenotype is highly specific for the MPO gene (PMID:15108282). Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP criteria applied:PVS1; PM3; PP4; BS1.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000265536	SCV001743601	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000265536	SCV001957582	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000265536	SCV001971230	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinic of Clinical Immunology with Stem Cell Bank, Expert Centre for Rare Diseases - PID, University Hospital "Alexandrovska"	RCV000003816	SCV002573417	likely pathogenic	Myeloperoxidase deficiency	2022-05-01	no assertion criteria provided	clinical testing
Undiagnosed Diseases Network, NIH	RCV000003816	SCV004242199	pathogenic	Myeloperoxidase deficiency	2023-05-22	no assertion criteria provided	clinical testing