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).
ClinVar Genomic variation as it relates to human health
NM_000250.2(MPO):c.1705C>T (p.Arg569Trp)
Germline
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.
(15)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic/Likely pathogenic
15
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000250.2(MPO):c.1705C>T (p.Arg569Trp)
Variation ID: 3626 Accession: VCV000003626.48
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 17q22 17: 58272835 (GRCh38) [ NCBI UCSC ] 17: 56350196 (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 Oct 20, 2024 Apr 4, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000250.2:c.1705C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000241.1:p.Arg569Trp missense NC_000017.11:g.58272835G>A NC_000017.10:g.56350196G>A NG_009629.1:g.13101C>T NG_044960.1:g.681G>A LRG_84:g.13101C>T LRG_84t1:c.1705C>T LRG_84p1:p.Arg569Trp P05164:p.Arg569Trp - Protein change
- R569W
- Other names
- -
- Canonical SPDI
- NC_000017.11:58272834:G:A
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
-
0.00040 (A)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
1000 Genomes Project 0.00040
1000 Genomes Project 30x 0.00047
The Genome Aggregation Database (gnomAD), exomes 0.00145
Exome Aggregation Consortium (ExAC) 0.00155
The Genome Aggregation Database (gnomAD) 0.00173
Trans-Omics for Precision Medicine (TOPMed) 0.00178
- 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. |
|||
| LOC106694316 | - | - | - | GRCh38 | - | 31 |
| MPO | - | - |
GRCh38 GRCh37 |
45 | 111 | |
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 (5) |
criteria provided, multiple submitters, no conflicts
|
Dec 26, 2021 | RCV000003810.13 | |
| Pathogenic/Likely pathogenic (8) |
criteria provided, multiple submitters, no conflicts
|
Apr 4, 2024 | RCV000366635.40 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Apr 11, 2022 | RCV002490304.3 | |
|
MPO-related disorder
|
Likely pathogenic (1) |
no assertion criteria provided
|
Apr 5, 2024 | RCV003415644.5 |
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. |
More information
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
(Apr 11, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Alzheimer disease type 1
Myeloperoxidase deficiency
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002780401.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
|
|
Likely pathogenic
(Dec 26, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Myeloperoxidase deficiency
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002023512.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
|
Pathogenic
(Aug 23, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Myeloperoxidase deficiency
(Autosomal recessive inheritance)
Affected status: no
Allele origin:
germline
|
Genetic Diagnostics Department, Viafet Genomics Laboratory
Accession: SCV001976439.1
First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021 |
Comment:
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 … (more)
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). (less)
Number of individuals with the variant: 1
Secondary finding: yes
|
|
|
Pathogenic
(May 20, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: unknown
Allele origin:
germline
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV002103266.1
First in ClinVar: Mar 12, 2022 Last updated: Mar 12, 2022 |
Comment:
PM3_very strong, PS3, PS4_moderate, PP3
|
|
|
Likely pathogenic
(Mar 08, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: yes
Allele origin:
germline
|
AiLife Diagnostics, AiLife Diagnostics
Accession: SCV002502200.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
Number of individuals with the variant: 2
Secondary finding: no
|
|
|
Pathogenic
(Apr 04, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000329997.8
First in ClinVar: Dec 06, 2016 Last updated: Sep 29, 2024 |
Comment:
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); … (more)
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) (less)
|
|
|
Pathogenic
(Jan 01, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001247509.26
First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024 |
Number of individuals with the variant: 3
|
|
|
Pathogenic
(May 01, 2004)
|
no assertion criteria provided
Method: literature only
|
MYELOPEROXIDASE DEFICIENCY
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000023975.4
First in ClinVar: Apr 04, 2013 Last updated: Dec 18, 2020 |
Comment on evidence:
In 6 of 7 patients with complete myeloperoxidase deficiency (MPOD; 254600), Nauseef et al. (1994) described a C-to-T substitution at nucleotide 8089 in exon 10 … (more)
In 6 of 7 patients with complete myeloperoxidase deficiency (MPOD; 254600), Nauseef et al. (1994) described a C-to-T substitution at nucleotide 8089 in exon 10 of the genomic sequence of MPO. At the amino acid level, the mutation replaced arginine at codon 569 with tryptophan (R569W). One patient was homozygous for the mutation, whereas the others were heterozygous. A seventh patient was the only completely deficient individual without the mutation. Independently, Kizaki et al. (1994) reported a 65-year-old Hispanic woman who was found to have MPO deficiency during routine blood examination by automated flow cytometry. The patient had no history of recurrent infections and was not taking medications known to interfere with MPO activity. Additional family members were not available for study. Granulocytes had no MPO activity and showed complete absence of mature and precursor MPO protein by Western blotting. By Southern blotting, a novel BglII fragment was detected. Direct sequencing of the PCR product of exon 10 showed a C-to-T transition at codon 569, resulting in an arginine (CGG)-to-tryptophan (TGG) substitution and creating a new BglII site. The mutation was homozygous. It was not found in 400 normal individuals. Nauseef et al. (1996) examined the consequences of the R569W mutation on MPO biosynthesis and processing, using stably transfected K562 cells expressing normal MPO or the R562W mutation. The authors concluded that the mutation results in a form of apopro-MPO that does not undergo posttranslational processing to enzymatically active MPO species. In 2 Italian patients with complete MPOD, 1 female (patient 2) and 1 male (patient 8), Marchetti et al. (2004) identified compound heterozygosity for the R569W mutation (c.1705C-T) and another mutation in the MPO gene: the 14-bp deletion (606989.0004) in patient 2, and the M251T substitution (606989.0003) in patient 8. (less)
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001744111.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021 |
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
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: SCV001952510.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
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: SCV001966910.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021 |
|
|
|
Pathogenic
(May 22, 2023)
|
no assertion criteria provided
Method: clinical testing
|
Myeloperoxidase deficiency
Affected status: yes
Allele origin:
paternal
|
Undiagnosed Diseases Network, NIH
Study: Undiagnosed Diseases Network (NIH), UDN
Accession: SCV004242198.1 First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024 |
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) , … (more)
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 abnormality (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) , Intellectual disability, severe (present) , Chronic sinusitis (present) , Dermatographic urticaria (present) , Abnormal autonomic nervous system physiology (present) , Fatigue (present) , Chronic constipation (present) (less)
Family history: no
Age: 30-39 years
Sex: female
Tissue: Blood
|
|
|
Likely pathogenic
(Apr 05, 2024)
|
no assertion criteria provided
Method: clinical testing
|
MPO-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004109188.2
First in ClinVar: Nov 20, 2023 Last updated: Oct 08, 2024 |
Comment:
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 … (more)
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. (less)
|
|
|
Likely pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
unknown
|
Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV001551737.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
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 … (more)
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. (less)
|
|
|
not provided
(-)
|
no classification provided
Method: phenotyping only
|
Myeloperoxidase deficiency
Affected status: yes
Allele origin:
paternal
|
GenomeConnect, ClinGen
Accession: SCV000607006.1
First in ClinVar: Oct 14, 2017 Last updated: Oct 14, 2017 |
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 … (more)
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)
Clinical Features:
Tall stature (present) , Growth hormone excess (present) , Growth hormone deficiency (present) , Failure to thrive (present) , Short stature (present) , Hemihypertrophy (present) … (more)
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) (less)
Indication for testing: Diagnostic
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
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Comment:
Comment:
PM3_very strong, PS3, PS4_moderate, PP3
Comment:
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)
Comment:
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.
Comment:
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.
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.
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
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).
Comment:
PM3_very strong, PS3, PS4_moderate, PP3
Comment:
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)
Comment:
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.
Comment:
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.
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 |
|---|---|---|---|---|
| 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 |
| Optimizing clinical exome design and parallel gene-testing for recessive genetic conditions in preconception carrier screening: Translational research genomic data from 14,125 exomes. | Capalbo A | PLoS genetics | 2019 | PMID: 31589614 |
| Homozygous calreticulin mutations in patients with myelofibrosis lead to acquired myeloperoxidase deficiency. | Theocharides AP | Blood | 2016 | PMID: 27013444 |
| Expression of myeloperoxidase enhances the chemosensitivity of leukemia cells through the generation of reactive oxygen species and the nitration of protein. | Sawayama Y | Leukemia | 2008 | PMID: 18273043 |
| Chronic granulomatous disease (CGD) and complete myeloperoxidase deficiency both yield strongly reduced dihydrorhodamine 123 test signals but can be easily discerned in routine testing for CGD. | Mauch L | Clinical chemistry | 2007 | PMID: 17384005 |
| Genetic characterization of myeloperoxidase deficiency in Italy. | Marchetti C | Human mutation | 2004 | PMID: 15108282 |
| Coordinated participation of calreticulin and calnexin in the biosynthesis of myeloperoxidase. | Nauseef WM | The Journal of biological chemistry | 1998 | PMID: 9507022 |
| Pattern of inheritance in hereditary myeloperoxidase deficiency associated with the R569W missense mutation. | Nauseef WM | Journal of leukocyte biology | 1998 | PMID: 9468285 |
| Effect of the R569W missense mutation on the biosynthesis of myeloperoxidase. | Nauseef WM | The Journal of biological chemistry | 1996 | PMID: 8621627 |
| Myeloperoxidase (MPO) gene mutation in hereditary MPO deficiency. | Kizaki M | Blood | 1994 | PMID: 8142659 |
| Hereditary myeloperoxidase deficiency due to a missense mutation of arginine 569 to tryptophan. | Nauseef WM | The Journal of biological chemistry | 1994 | PMID: 7904599 |
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Text-mined citations for rs119468010 ...
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Record last updated Oct 20, 2024
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.