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.
ClinVar Genomic variation as it relates to human health
NM_000250.2(MPO):c.2031-2A>C
Germline
Classification
Help
criteria provided, conflicting classifications. Learn more about how ClinVar calculates review status.
Conflicting classifications of pathogenicity
Pathogenic(8); Likely pathogenic(5); Uncertain significance(1)
Pathogenic(8); Likely pathogenic(5); Uncertain significance(1)
14 out of 30 submissions contributed to this classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
23
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
This variant is part of a Genotype
- Identifiers
-
NM_000250.2(MPO):c.2031-2A>C
Variation ID: 3632 Accession: VCV000003632.71
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 17q22 17: 58270865 (GRCh38) [ NCBI UCSC ] 17: 56348226 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Jul 5, 2015 Jan 11, 2026 Sep 1, 2025 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000250.2:c.2031-2A>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
splice acceptor NC_000017.11:g.58270865T>G NC_000017.10:g.56348226T>G NG_009629.1:g.15071A>C LRG_84:g.15071A>C LRG_84t1:c.2031-2A>C - Protein change
- -
- Other names
-
IVS11AS, A-C, -2
- Canonical SPDI
- NC_000017.11:58270864:T:G
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
-
0.00080 (G)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
1000 Genomes Project 30x 0.00062
1000 Genomes Project 0.00080
Trans-Omics for Precision Medicine (TOPMed) 0.00400
Exome Aggregation Consortium (ExAC) 0.00426
The Genome Aggregation Database (gnomAD), exomes 0.00437
The Genome Aggregation Database (gnomAD) 0.00456
The Genome Aggregation Database (gnomAD) 0.00472
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00523
The Genome Aggregation Database (gnomAD), exomes 0.00568
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| LPO | - | - |
GRCh38 GRCh37 |
121 | 138 | |
| MPO | - | - |
GRCh38 GRCh37 |
81 | 174 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic/Likely pathogenic (12) |
criteria provided, multiple submitters, no conflicts
|
Feb 27, 2025 | RCV000003816.34 | |
| Pathogenic/Likely pathogenic (8) |
criteria provided, multiple submitters, no conflicts
|
Sep 1, 2025 | RCV000265536.53 | |
|
MPO-related disorder
|
Pathogenic (1) |
no assertion criteria provided
|
Sep 5, 2024 | RCV003398437.6 |
| Pathogenic (1) |
criteria provided, single submitter
|
Apr 12, 2022 | RCV002482823.8 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
May 1, 2024 | RCV004689407.1 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
Expand all rows
Collapse all rows
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Sep 26, 2014)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Myeloperoxidase deficiency
(Autosomal recessive inheritance)
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Study: CSER-MedSeq
Accession: SCV000221199.2 First in ClinVar: Apr 01, 2015 Last updated: Jul 05, 2015 |
Comment:
show
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. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: not provided
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: not provided
Number of individuals with the variant: 2
|
|
|
Likely pathogenic
(Mar 30, 2022)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
AiLife Diagnostics, AiLife Diagnostics
Accession: SCV002502221.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Number of individuals with the variant: 3
Secondary finding: no
Platform type: NGS
|
|
|
Uncertain significance
(May 01, 2024)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
not specified |
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV005184390.1
First in ClinVar: Aug 11, 2024 Last updated: Aug 11, 2024 |
Comment:
show
Variant summary: MPO c.2031-2A>C is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes the canonical 3' acceptor site. At least one publication reports experimental evidence that this variant affects mRNA splicing , and the predominant products were truncated MPO (Haskamp_2020), such mRNA products are not subject to NMD. The variant allele was found at a frequency of 0.0044 in 251174 control chromosomes in the gnomAD database, including 2 homozygotes (gnomAD v2), and in gnomAD v4 dataset, this vairant was found a frequency of 0.0066 in 1179978 control chromosomes in European (non-Finnish) group with 25 homozygotes, suggesting that the variant may be benign. c.2031-2A>C has been reported in the literature in at-least three individuals affected with Myeloperoxidase Deficiency (example, Marchetti_2004). Additionally, no pathogenic missense or in-frame changes from the last exon have been reported in ClinVar, suggesting the disrupted last exon may not be functionally important. The following publications have been ascertained in the context of this evaluation (PMID: 32758447, 15108282). ClinVar contains an entry for this variant (Variation ID: 3632). Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Pathogenic
(Mar 01, 2023)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Myeloperoxidase deficiency |
Payam Genetics Center, General Welfare Department of North Khorasan Province
Accession: SCV003924023.2
First in ClinVar: May 13, 2023 Last updated: Apr 13, 2025 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Number of individuals with the variant: 1
Age: 0-9 years
Sex: male
Ethnicity/Population group: Iranian
Geographic origin: Iran
|
|
|
Pathogenic
(Jul 25, 2023)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Myeloperoxidase deficiency |
Department of Pathology and Laboratory Medicine, Sinai Health System
Accession: SCV005921007.1
First in ClinVar: Apr 28, 2025 Last updated: Apr 28, 2025 |
Observation: 1
Collection method: research
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: research
Allele origin: germline
Affected status: unknown
|
|
|
Pathogenic
(Feb 16, 2025)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
Laboratory of Genetics, Children's Clinical University Hospital Latvia
Accession: SCV006109971.1
First in ClinVar: Jul 05, 2025 Last updated: Jul 05, 2025 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
|
Likely pathogenic
(Feb 27, 2025)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Myeloperoxidase deficiency |
Revvity Omics, Revvity
Accession: SCV002023510.4
First in ClinVar: Nov 29, 2021 Last updated: Sep 06, 2025 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Likely pathogenic
(Jan 01, 2019)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Myeloperoxidase deficiency |
Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV001439966.1
First in ClinVar: Oct 31, 2020 Last updated: Oct 31, 2020 |
Observation: 1
Collection method: clinical testing
Allele origin: unknown
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: unknown
Affected status: yes
|
|
|
Pathogenic
(Apr 12, 2022)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Alzheimer disease type 1
Myeloperoxidase deficiency |
Fulgent Genetics, Fulgent Genetics
Accession: SCV002778311.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
Observation: 1
Collection method: clinical testing
Allele origin: unknown
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: unknown
Affected status: unknown
|
|
|
Pathogenic
(Nov 03, 2021)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden
Accession: SCV002009349.3
First in ClinVar: Nov 06, 2021 Last updated: Jul 16, 2023 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: not provided
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: not provided
|
|
|
Pathogenic
(Mar 26, 2024)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Myeloperoxidase deficiency |
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre
Accession: SCV004806673.1
First in ClinVar: Apr 06, 2024 Last updated: Apr 06, 2024 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Likely pathogenic
(Jul 08, 2019)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Myeloperoxidase deficiency |
Knight Diagnostic Laboratories, Oregon Health and Sciences University
Accession: SCV001448821.2
First in ClinVar: Dec 12, 2020 Last updated: Apr 13, 2025 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Number of individuals with the variant: 1
Clinical Features:
Seizures (present) , Language impairment (present) , Speech articulation difficulties (present) , Global developmental delay (present) , Abnormality of the optic nerve (present) , Delayed speech and language development (present) , Short stature (present) , Chronic diarrhea (present) , Dolichocephaly (present) , Deeply set eye (present) , Frontal bossing (present) , Generalized hypotonia (present) , Small for gestational age (present) , Recurrent hypoglycemia (present) , Episodic fever (present) , Lactic acidosis (present) , Chronic neutropenia (present) , Motor aphasia (present) , Recurrent bacterial skin infections (present)
Sex: male
|
|
|
Pathogenic
(May 27, 2025)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
GeneDx
Accession: SCV000329427.12
First in ClinVar: Dec 06, 2016 Last updated: Jun 29, 2025 |
Comment:
show
Reported as a heterozygous germline variant in multiple individuals with myeloid neoplasms (PMID: 35761024); 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 (PMID: 15108282); Canonical splice site variant predicted to result in an in-frame loss of the adjacent exon in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 20974672, 25714468, 34662886, 35026467, 24385801, 17384005, 15108282, 26764160, 26822949, 27301573, 27827828, 30487145, 31980526, 32758448, 34426522, 32531373, 35761024, 36730508, 37868038, 38170104, 32758447) (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
|
Likely pathogenic
(Sep 01, 2025)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001334657.35
First in ClinVar: Jun 08, 2020 Last updated: Jan 11, 2026 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Number of individuals with the variant: 8
|
|
|
Pathogenic
(May 01, 2004)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
MYELOPEROXIDASE DEFICIENCY |
OMIM
Accession: SCV000023981.4
First in ClinVar: Apr 04, 2013 Last updated: Dec 19, 2020 |
Observation: 1
Collection method: literature only
Allele origin: germline
Affected status: not provided
Observation 1
Collection method: literature only
Allele origin: germline
Affected status: not provided
Comment on evidence:
In 2 female Italian patients (patients 1 and 7) with complete myeloperoxidase deficiency (MPOD; 254600), Marchetti et al. (2004) identified homozygosity for a 2031A-C transversion … (more)
In 2 female Italian patients (patients 1 and 7) with complete myeloperoxidase deficiency (MPOD; 254600), Marchetti et al. (2004) identified homozygosity for a 2031A-C transversion in the 3-prime splice site of intron 11 of the MPO gene (IVS11AS-2A-C). In a third patient (patient 13) with complete MPOD, they identified the IVS11AS-2A-C transversion in compound heterozygous state with a 14-bp deletion in exon 9 of the MPO gene (606989.0004). Because of difficulty in obtaining bone marrow samples from MPO-deficient patients to study MPO mRNA splicing in vivo, the authors set up a eukaryotic expression system to investigate how the IVS11AS-2-A-C mutation alters MPO pre-mRNA splicing. Activation of a cryptic 3-prime splice site located 109 bp upstream of the authentic 3-prime splice site was observed. The 109-bp insertion caused a frameshift, resulting in a premature stop codon and an abnormal MPO precursor lacking enzymatic activity. (less)
|
|
|
Pathogenic
(-)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
not provided |
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001957582.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
|
Pathogenic
(-)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
not provided |
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001971230.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
|
Pathogenic
(Sep 05, 2024)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
MPO-related condition
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004104737.3
First in ClinVar: Nov 20, 2023 Last updated: Oct 08, 2024 |
Comment:
show
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. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Pathogenic
(Jan 06, 2020)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
Myeloperoxidase deficiency |
Reproductive Health Research and Development, BGI Genomics
Accession: SCV001142475.1
First in ClinVar: Jan 13, 2020 Last updated: Jan 13, 2020 |
Comment:
show
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. (less)
Observation: 1
Collection method: curation
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: curation
Allele origin: germline
Affected status: unknown
|
|
|
Likely pathogenic
(-)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
not provided |
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001743601.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
|
Likely pathogenic
(May 01, 2022)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
Myeloperoxidase deficiency |
Clinic of Clinical Immunology with Stem Cell Bank, Expert Centre for Rare Diseases - PID, University Hospital "Alexandrovska"
Accession: SCV002573417.1
First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
|
Pathogenic
(May 22, 2023)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
Myeloperoxidase deficiency |
Undiagnosed Diseases Network, NIH
Study: Undiagnosed Diseases Network (NIH), UDN
Accession: SCV004242199.2 First in ClinVar: Feb 04, 2024 Last updated: Apr 13, 2025 |
Observation: 1
Collection method: clinical testing
Allele origin: maternal
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: maternal
Affected status: yes
Number of individuals with the variant: 1
Clinical Features:
Recurrent urinary tract infections (present) , Neurogenic bladder (present) , Urinary retention (present) , Autism (present) , Impaired social interactions (present) , Pruritus (present) , Seizure (present) , Absent speech (present) , Obesity (present) , Iron deficiency anemia (present) , Hyperammonemia (present) , Gastroesophageal reflux (present) , Abdominal pain (present) , Hiatus hernia (present) , Broad-based gait (present) , Aganglionic megacolon (present) , Headache (present) , Sleep disturbance (present) , Developmental regression (present) , Episodic vomiting (present) , Gastroparesis (present) , Gastrointestinal dysmotility (present) , Recurrent infections (present) , Recurrent candida infections (present) , Focal emotional seizure with laughing (present) , Severe intellectual disability (present) , Chronic sinusitis (present) , Dermatographic urticaria (present) , Abnormal autonomic nervous system physiology (present) , Fatigue (present) , Chronic constipation (present)
Zygosity: Compound Heterozygote
Family history: no
Age: 30-39 years
Sex: female
Tissue: Blood
|
|
|
not provided
(-)
N
Not contributing to aggregate classification
|
no classification provided
|
Myeloperoxidase deficiency |
GenomeConnect, ClinGen
Accession: SCV000607007.2
First in ClinVar: Oct 14, 2017 Last updated: Apr 13, 2025 |
Comment:
show
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. (less)
Observation: 1
Collection method: phenotyping only
Allele origin: maternal
Affected status: yes
Observation 1
Collection method: phenotyping only
Allele origin: maternal
Affected status: yes
Clinical Features:
Tall stature (present) , Growth hormone excess (present) , Growth hormone deficiency (present) , Failure to thrive (present) , Short stature (present) , Hemihypertrophy (present) , Obesity (present) , Overgrowth (present) , Abnormality of the parathyroid physiology (present) , Hyperthyroidism (present) , Goiter (present) , Adrenal hyperplasia (present) , Hypogonadism (present) , Precocious puberty (present) , Diabetes insipidus (present) , Delayed puberty (present) , Type I diabetes mellitus (present) , Type II diabetes mellitus (present) , Oral-pharyngeal dysphagia (present) , Abnormality of the neck (present) , Abnormality of the mouth (present) , Abnormality of the oral cavity (present) , Abnormality of the optic nerve (present) , Hypermetropia (present) , Myopia (present) , Abnormality of vision (present) , Abnormality of eye movement (present) , Vertigo (present) , Tinnitus (present) , Sensorineural hearing impairment (present) , Abnormality of movement (present) , Memory impairment (present) , Abnormality of coordination (present) , Cognitive impairment (present) , Anxiety (present) , Autistic behavior (present) , Hyperpigmentation of the skin (present) , Multiple cafe-au-lait spots (present) , Joint hypermobility (present) , Abnormality of the curvature of the vertebral column (present) , Abnormality of muscle physiology (present) , Hypercholesterolemia (present) , Hypertension (present) , Abnormality of cardiovascular system morphology (present) , Syncope (present) , Cardiomyopathy (present) , Abnormal EKG (present) , Arrhythmia (present) , Asthma (present) , Abnormality of the intestine (present) , Gastrointestinal dysmotility (present) , Abnormality of the liver (present) , Abnormality of the stomach (present) , Abnormality of esophagus morphology (present) , Feeding difficulties (present) , Abnormality of urine homeostasis (present) , Abnormal renal morphology (present) , Abnormality of the bladder (present) , Rheumatoid arthritis (present) , Recurrent infections (present) , Abnormal inflammatory response (present) , Autoimmunity (present) , Abnormality of leukocytes (present) , Abnormality of erythrocytes (present) , Bleeding with minor or no trauma (present) , Abnormality of blood and blood-forming tissues (present)
Indication for testing: Diagnostic
Test name: Exome Sequencing
Age: 40-49 years
Sex: female
Method: Sanger Sequencing
Testing laboratory: GeneDx
Date variant was reported to submitter: 2016-09-09
Testing laboratory interpretation: Pathogenic
|
|
Comment:
Comment:
Variant summary: MPO c.2031-2A>C is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes the canonical 3' acceptor site. At least one publication reports experimental evidence that this variant affects mRNA splicing , and the predominant products were truncated MPO (Haskamp_2020), such mRNA products are not subject to NMD. The variant allele was found at a frequency of 0.0044 in 251174 control chromosomes in the gnomAD database, including 2 homozygotes (gnomAD v2), and in gnomAD v4 dataset, this vairant was found a frequency of 0.0066 in 1179978 control chromosomes in European (non-Finnish) group with 25 homozygotes, suggesting that the variant may be benign. c.2031-2A>C has been reported in the literature in at-least three individuals affected with Myeloperoxidase Deficiency (example, Marchetti_2004). Additionally, no pathogenic missense or in-frame changes from the last exon have been reported in ClinVar, suggesting the disrupted last exon may not be functionally important. The following publications have been ascertained in the context of this evaluation (PMID: 32758447, 15108282). ClinVar contains an entry for this variant (Variation ID: 3632). Based on the evidence outlined above, the variant was classified as uncertain significance.
Comment:
This variant was identified as compound heterozygous.
Comment:
Reported as a heterozygous germline variant in multiple individuals with myeloid neoplasms (PMID: 35761024); 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 (PMID: 15108282); Canonical splice site variant predicted to result in an in-frame loss of the adjacent exon in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 20974672, 25714468, 34662886, 35026467, 24385801, 17384005, 15108282, 26764160, 26822949, 27301573, 27827828, 30487145, 31980526, 32758448, 34426522, 32531373, 35761024, 36730508, 37868038, 38170104, 32758447)
Comment:
MPO: PM3, PS3:Moderate, PM2:Supporting, PP3
Comment:
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.
Comment:
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.
Comment:
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.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| The genetic structure of the Turkish population reveals high levels of variation and admixture. | Kars ME | Proceedings of the National Academy of Sciences of the United States of America | 2021 | PMID: 34426522 |
| Improving the diagnostic efficiency of primary immunodeficiencies with targeted next-generation sequencing. | Fusaro M | The Journal of allergy and clinical immunology | 2021 | PMID: 32531373 |
| Loss-of-Function Myeloperoxidase Mutations Are Associated with Increased Neutrophil Counts and Pustular Skin Disease. | Vergnano M | American journal of human genetics | 2020 | PMID: 32758448 |
| Myeloperoxidase Modulates Inflammation in Generalized Pustular Psoriasis and Additional Rare Pustular Skin Diseases. | Haskamp S | American journal of human genetics | 2020 | PMID: 32758447 |
| Precision medicine integrating whole-genome sequencing, comprehensive metabolomics, and advanced imaging. | Hou YC | Proceedings of the National Academy of Sciences of the United States of America | 2020 | PMID: 31980526 |
| High-frequency actionable pathogenic exome variants in an average-risk cohort. | Rego S | Cold Spring Harbor molecular case studies | 2018 | PMID: 30487145 |
| Hereditary truncating mutations of DNA repair and other genes in BRCA1/BRCA2/PALB2-negatively tested breast cancer patients. | Lhota F | Clinical genetics | 2016 | PMID: 26822949 |
| 267 Spanish Exomes Reveal Population-Specific Differences in Disease-Related Genetic Variation. | Dopazo J | Molecular biology and evolution | 2016 | PMID: 26764160 |
| Genetic characterization of myeloperoxidase deficiency in Italy. | Marchetti C | Human mutation | 2004 | PMID: 15108282 |
| Clinical manifestation of myeloperoxidase deficiency. | Lanza F | Journal of molecular medicine (Berlin, Germany) | 1998 | PMID: 9766845 |
| Hereditary myeloperoxidase deficiency. | Kitahara M | Blood | 1981 | PMID: 6260268 |
| click to load more citations click to collapse | ||||
Submissions - Functional Data
functionally abnormal
--
retained intron
assessed by
RNAseq
Result:
junction spanning - intron inclusion with mutation (p=0.0)
Modifies a natural acceptor site at NC_000017.10:g.56348225 from 4.07 to -14.55 bits. Significant p-values: junction spanning - intron inclusion with mutation (589 reads, p=0.0). Computations were originally performed using genomic coordinates. This variant was mapped to an appropriate current MANE database designation or, if not present in this source, to the longest relevant transcript in the Biocommons Universal Transcript Archive using the hgvs Python package. The original genomic coordinate was based on GRCh37 and was submitted as an "Alternate designation". Modifications of Figure 2 of PMID:31275557 for ClinVar: a) "strongly corroborating Veridical p-value" refers to "junction-spanning" evidence types; b) add the text "and natural site < 300 nucleotides away?" to "Ri,final > nearest natural site Ri"; c) "Aberrant" and "Likely aberrant" classifications are now both defined as "Functionally abnormal" (analogous to ACMG/AMP reporting); d) "Allele-specific alternative splicing" classification now defined as "Function uncertain" (based on results for similar variants in PMID: 32211018); e) average heterozygosity based-criteria no longer contribute to classification.
Citation:
PubMed: 31275557
Accession: SCV006890934.1
Submitted: 2025-10-17
Assay description:
In the sample (TCGA-AB-2848), the counts of splice junction spanning reads and abundance of the transcript adjacent to this mutation were compared with RNASeq data from matched tissues and tumors lacking the same mutation using Veridical (PMID:24741438)
- Disease context: Acute myeloid leukemia
- Transcript: NM_000250.2:c.2031-2A>C
- Molecular phenotype measured: splicing
- Cell line: TCGA-AB-2848
- Tissue: Acute Myeloid Leukemia (LAML)
- Collection method: in vitro
- Species: human
- Number of controls: 185
functionally abnormal
--
retained intron
assessed by
RNAseq
Result:
junction spanning - intron inclusion with mutation (p=0.0164)
Modifies a natural acceptor site at NC_000017.10:g.56348225 from 4.07 to -14.55 bits. Significant p-values: junction spanning - intron inclusion with mutation (36 reads, p=0.0164). Computations were originally performed using genomic coordinates. This variant was mapped to an appropriate current MANE database designation or, if not present in this source, to the longest relevant transcript in the Biocommons Universal Transcript Archive using the hgvs Python package. The original genomic coordinate was based on GRCh37 and was submitted as an "Alternate designation". Modifications of Figure 2 of PMID:31275557 for ClinVar: a) "strongly corroborating Veridical p-value" refers to "junction-spanning" evidence types; b) add the text "and natural site < 300 nucleotides away?" to "Ri,final > nearest natural site Ri"; c) "Aberrant" and "Likely aberrant" classifications are now both defined as "Functionally abnormal" (analogous to ACMG/AMP reporting); d) "Allele-specific alternative splicing" classification now defined as "Function uncertain" (based on results for similar variants in PMID: 32211018); e) average heterozygosity based-criteria no longer contribute to classification.
Citation:
PubMed: 31275557
Accession: SCV006890935.1
Submitted: 2025-10-17
Assay description:
In the sample (TCGA-AB-2904), the counts of splice junction spanning reads and abundance of the transcript adjacent to this mutation were compared with RNASeq data from matched tissues and tumors lacking the same mutation using Veridical (PMID:24741438)
- Disease context: Acute myeloid leukemia
- Transcript: NM_000250.2:c.2031-2A>C
- Molecular phenotype measured: splicing
- Cell line: TCGA-AB-2904
- Tissue: Acute Myeloid Leukemia (LAML)
- Collection method: in vitro
- Species: human
- Number of controls: 185
functionally abnormal
--
retained intron
assessed by
RNAseq
Result:
junction spanning - intron inclusion with mutation (p=0.0)
Modifies a natural acceptor site at NC_000017.10:g.56348225 from 4.07 to -14.55 bits. Significant p-values: junction spanning - intron inclusion with mutation (237 reads, p=0.0). Computations were originally performed using genomic coordinates. This variant was mapped to an appropriate current MANE database designation or, if not present in this source, to the longest relevant transcript in the Biocommons Universal Transcript Archive using the hgvs Python package. The original genomic coordinate was based on GRCh37 and was submitted as an "Alternate designation". Modifications of Figure 2 of PMID:31275557 for ClinVar: a) "strongly corroborating Veridical p-value" refers to "junction-spanning" evidence types; b) add the text "and natural site < 300 nucleotides away?" to "Ri,final > nearest natural site Ri"; c) "Aberrant" and "Likely aberrant" classifications are now both defined as "Functionally abnormal" (analogous to ACMG/AMP reporting); d) "Allele-specific alternative splicing" classification now defined as "Function uncertain" (based on results for similar variants in PMID: 32211018); e) average heterozygosity based-criteria no longer contribute to classification.
Citation:
PubMed: 31275557
Accession: SCV006890936.1
Submitted: 2025-10-17
Assay description:
In the sample (TCGA-AB-2964), the counts of splice junction spanning reads and abundance of the transcript adjacent to this mutation were compared with RNASeq data from matched tissues and tumors lacking the same mutation using Veridical (PMID:24741438)
- Disease context: Acute myeloid leukemia
- Transcript: NM_000250.2:c.2031-2A>C
- Molecular phenotype measured: splicing
- Cell line: TCGA-AB-2964
- Tissue: Acute Myeloid Leukemia (LAML)
- Collection method: in vitro
- Species: human
- Number of controls: 185
functionally abnormal
--
retained intron
assessed by
RNAseq
Result:
junction spanning - intron inclusion with mutation (p=0.0338),read abundance - intron inclusion (p=0.0001)
Modifies a natural acceptor site at NC_000017.10:g.56348225 from 4.07 to -14.55 bits. Significant p-values: junction spanning - intron inclusion with mutation (1 reads, p=0.0338), read abundance - intron inclusion (8 reads, p=0.0001). Computations were originally performed using genomic coordinates. This variant was mapped to an appropriate current MANE database designation or, if not present in this source, to the longest relevant transcript in the Biocommons Universal Transcript Archive using the hgvs Python package. The original genomic coordinate was based on GRCh37 and was submitted as an "Alternate designation". Modifications of Figure 2 of PMID:31275557 for ClinVar: a) "strongly corroborating Veridical p-value" refers to "junction-spanning" evidence types; b) add the text "and natural site < 300 nucleotides away?" to "Ri,final > nearest natural site Ri"; c) "Aberrant" and "Likely aberrant" classifications are now both defined as "Functionally abnormal" (analogous to ACMG/AMP reporting); d) "Allele-specific alternative splicing" classification now defined as "Function uncertain" (based on results for similar variants in PMID: 32211018); e) average heterozygosity based-criteria no longer contribute to classification.
Citation:
PubMed: 31275557
Accession: SCV006890937.1
Submitted: 2025-10-17
Assay description:
In the sample (TCGA-4X-A9FB), the counts of splice junction spanning reads and abundance of the transcript adjacent to this mutation were compared with RNASeq data from matched tissues and tumors lacking the same mutation using Veridical (PMID:24741438)
- Disease context: Thymoma
- Transcript: NM_000250.2:c.2031-2A>C
- Molecular phenotype measured: splicing
- Cell line: TCGA-4X-A9FB
- Tissue: Thymoma (THYM)
- Collection method: in vitro
- Species: human
- Number of controls: 35
functionally abnormal
--
retained intron
assessed by
RNAseq
Result:
junction spanning - intron inclusion with mutation (p=0.0),read abundance - intron inclusion (p=0.0281)
Modifies a natural acceptor site at NC_000017.10:g.56348225 from 4.07 to -14.55 bits. Significant p-values: junction spanning - intron inclusion with mutation (2 reads, p=0.0), read abundance - intron inclusion (8 reads, p=0.0281). Computations were originally performed using genomic coordinates. This variant was mapped to an appropriate current MANE database designation or, if not present in this source, to the longest relevant transcript in the Biocommons Universal Transcript Archive using the hgvs Python package. The original genomic coordinate was based on GRCh37 and was submitted as an "Alternate designation". Modifications of Figure 2 of PMID:31275557 for ClinVar: a) "strongly corroborating Veridical p-value" refers to "junction-spanning" evidence types; b) add the text "and natural site < 300 nucleotides away?" to "Ri,final > nearest natural site Ri"; c) "Aberrant" and "Likely aberrant" classifications are now both defined as "Functionally abnormal" (analogous to ACMG/AMP reporting); d) "Allele-specific alternative splicing" classification now defined as "Function uncertain" (based on results for similar variants in PMID: 32211018); e) average heterozygosity based-criteria no longer contribute to classification.
Citation:
PubMed: 31275557
Accession: SCV006890938.1
Submitted: 2025-10-17
Assay description:
In the sample (TCGA-24-1467), the counts of splice junction spanning reads and abundance of the transcript adjacent to this mutation were compared with RNASeq data from matched tissues and tumors lacking the same mutation using Veridical (PMID:24741438)
- Disease context: Ovarian serous cystadenocarcinoma
- Transcript: NM_000250.2:c.2031-2A>C
- Molecular phenotype measured: splicing
- Cell line: TCGA-24-1467
- Tissue: Ovarian Cancer (OV)
- Collection method: in vitro
- Species: human
- Number of controls: 154
functionally abnormal
--
retained intron
assessed by
RNAseq
Result:
read abundance - intron inclusion (p=0.0182)
Modifies a natural acceptor site at NC_000017.10:g.56348225 from 4.07 to -14.55 bits. Significant p-values: read abundance - intron inclusion (10 reads, p=0.0182). Computations were originally performed using genomic coordinates. This variant was mapped to an appropriate current MANE database designation or, if not present in this source, to the longest relevant transcript in the Biocommons Universal Transcript Archive using the hgvs Python package. The original genomic coordinate was based on GRCh37 and was submitted as an "Alternate designation". Modifications of Figure 2 of PMID:31275557 for ClinVar: a) "strongly corroborating Veridical p-value" refers to "junction-spanning" evidence types; b) add the text "and natural site < 300 nucleotides away?" to "Ri,final > nearest natural site Ri"; c) "Aberrant" and "Likely aberrant" classifications are now both defined as "Functionally abnormal" (analogous to ACMG/AMP reporting); d) "Allele-specific alternative splicing" classification now defined as "Function uncertain" (based on results for similar variants in PMID: 32211018); e) average heterozygosity based-criteria no longer contribute to classification.
Citation:
PubMed: 31275557
Accession: SCV006890939.1
Submitted: 2025-10-17
Assay description:
In the sample (TCGA-N9-A4Q3), the counts of splice junction spanning reads and abundance of the transcript adjacent to this mutation were compared with RNASeq data from matched tissues and tumors lacking the same mutation using Veridical (PMID:24741438)
- Disease context: Uterine carcinosarcoma
- Transcript: NM_000250.2:c.2031-2A>C
- Molecular phenotype measured: splicing
- Cell line: TCGA-N9-A4Q3
- Tissue: Uterine Carcinosarcoma (UCS)
- Collection method: in vitro
- Species: human
- Number of controls: 36
functionally abnormal
--
retained intron
assessed by
RNAseq
Result:
junction spanning - intron inclusion with mutation (p=0.0)
Modifies a natural acceptor site at NC_000017.10:g.56348225 from 4.07 to -14.55 bits. Significant p-values: junction spanning - intron inclusion with mutation (2 reads, p=0.0). Computations were originally performed using genomic coordinates. This variant was mapped to an appropriate current MANE database designation or, if not present in this source, to the longest relevant transcript in the Biocommons Universal Transcript Archive using the hgvs Python package. The original genomic coordinate was based on GRCh37 and was submitted as an "Alternate designation". Modifications of Figure 2 of PMID:31275557 for ClinVar: a) "strongly corroborating Veridical p-value" refers to "junction-spanning" evidence types; b) add the text "and natural site < 300 nucleotides away?" to "Ri,final > nearest natural site Ri"; c) "Aberrant" and "Likely aberrant" classifications are now both defined as "Functionally abnormal" (analogous to ACMG/AMP reporting); d) "Allele-specific alternative splicing" classification now defined as "Function uncertain" (based on results for similar variants in PMID: 32211018); e) average heterozygosity based-criteria no longer contribute to classification.
Citation:
PubMed: 31275557
Accession: SCV006890940.1
Submitted: 2025-10-17
Assay description:
In the sample (TCGA-L5-A893), the counts of splice junction spanning reads and abundance of the transcript adjacent to this mutation were compared with RNASeq data from matched tissues and tumors lacking the same mutation using Veridical (PMID:24741438)
- Disease context: Malignant tumor of esophagus
- Transcript: NM_000250.2:c.2031-2A>C
- Molecular phenotype measured: splicing
- Cell line: TCGA-L5-A893
- Tissue: Esophageal Carcinoma (ESCA)
- Collection method: in vitro
- Species: human
- Number of controls: 70
Text-mined citations for rs35897051 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Jan 11, 2026
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.