chr17-58272835-G-A

Variant names:

• chr17-58272835-G-A
• rs119468010
• NM_000250.2:c.1705C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 9P and 2B. PP3 PP5_Very_Strong BP4 BS2_Supporting

The NM_000250.2(MPO):​c.1705C>T​(p.Arg569Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00266 in 1,614,180 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.0017 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0028 (5 hom.)
• Consequence: MPO NM_000250.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14 O:1
• Conservation: PhyloP100: 4.28
• Publications: 33 publications found

Genes affected

MPO (HGNC:7218): (myeloperoxidase) Myeloperoxidase (MPO) is a heme protein synthesized during myeloid differentiation that constitutes the major component of neutrophil azurophilic granules. Produced as a single chain precursor, myeloperoxidase is subsequently cleaved into a light and heavy chain. The mature myeloperoxidase is a tetramer composed of 2 light chains and 2 heavy chains. This enzyme produces hypohalous acids central to the microbicidal activity of neutrophils. [provided by RefSeq, Nov 2014]

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 8: AlphaMissense, BayesDel_noAF, Cadd, Dann, Eigen, PROVEAN, REVEL, REVEL [when BayesDel_addAF, max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• PP5: Variant 17-58272835-G-A is Pathogenic according to our data. Variant chr17-58272835-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 3626.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.112965494). . Strength limited to SUPPORTING due to the PP5.
• BS2: High Homozygotes in GnomAdExome4 at 5 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000250.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MPO	NM_000250.2	MANE Select	c.1705C>T	p.Arg569Trp	missense	Exon 10 of 12	NP_000241.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MPO	ENST00000225275.4	TSL:1 MANE Select	c.1705C>T	p.Arg569Trp	missense	Exon 10 of 12	ENSP00000225275.3
	MPO	ENST00000577220.1	TSL:3	c.163C>T	p.Arg55Trp	missense	Exon 2 of 3	ENSP00000464668.1
	MPO	ENST00000578493.2	TSL:3	n.1038C>T		non_coding_transcript_exon	Exon 5 of 7

Frequencies

GnomAD3 genomes AF: 0.00168 AC: 255 AN: 152196 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000700

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000719

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00306

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00145 AC: 365 AN: 251472 AF XY: 0.00140

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.000405

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000554

Gnomad NFE exome AF: 0.00286

Gnomad OTH exome AF: 0.000978

GnomAD4 exome AF: 0.00276 AC: 4031 AN: 1461866 Hom.: 5 Cov.: 31 AF XY: 0.00262 AC XY: 1903 AN XY: 727232

African (AFR) AF: 0.000329 AC: 11 AN: 33480

American (AMR) AF: 0.000447 AC: 20 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000115 AC: 3 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.000290 AC: 25 AN: 86256

European-Finnish (FIN) AF: 0.000524 AC: 28 AN: 53398

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.00343 AC: 3810 AN: 1112012

Other (OTH) AF: 0.00217 AC: 131 AN: 60394

GnomAD4 genome AF: 0.00167 AC: 255 AN: 152314 Hom.: 0 Cov.: 32 AF XY: 0.00138 AC XY: 103 AN XY: 74486

African (AFR) AF: 0.000698 AC: 29 AN: 41554

American (AMR) AF: 0.000718 AC: 11 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5188

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4824

European-Finnish (FIN) AF: 0.000282 AC: 3 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00306 AC: 208 AN: 68028

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.00250 Hom.: 3

Bravo AF: 0.00178

TwinsUK AF: 0.00405 AC: 15

ALSPAC AF: 0.00493 AC: 19

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00291 AC: 25

ExAC AF: 0.00155 AC: 188

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00234

EpiControl AF: 0.00202

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:14 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:8

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: 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.

May 20, 2021

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM3_very strong, PS3, PS4_moderate, PP3

Mar 27, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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, 36730508, 35761024, 8621627)

Jan 01, 2021

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Mar 08, 2022

AiLife Diagnostics, AiLife Diagnostics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Myeloperoxidase deficiency Pathogenic:4 Other:1

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: 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.

Aug 23, 2021

Genetic Diagnostics Department, Viafet Genomics Laboratory

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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).

Aug 08, 2024

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

May 01, 2004

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

May 22, 2023

Undiagnosed Diseases Network, NIH

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Myeloperoxidase deficiency;C1863052:Alzheimer disease type 1 Pathogenic:1

Apr 11, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MPO-related disorder Pathogenic:1

Apr 05, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: 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.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Benign	-0.0064	T
BayesDel_noAF	Pathogenic	0.22
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.85	D
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.11	T
MetaSVM	Uncertain	0.45	D
MutationAssessor	Uncertain	2.9	M
PhyloP100		4.3
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-5.6	D
REVEL	Pathogenic	0.76
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.95
MVP		0.99
MPC		1.0
ClinPred		0.063	T
GERP RS		5.1
Varity_R		0.93
gMVP		0.83
Mutation Taster		=21/79	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs119468010; hg19: chr17-56350196; COSMIC: COSV104554515; COSMIC: COSV104554515;