PGM3

protein-coding

phosphoglucomutase 3

Gene summary

This gene encodes a member of the phosphohexose mutase family. The encoded protein mediates both glycogen formation and utilization by catalyzing the interconversion of glucose-1-phosphate and glucose-6-phosphate. A non-synonymous single nucleotide polymorphism in this gene may play a role in resistance to diabetic nephropathy and neuropathy. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Dec 2010]

MANE transcript

NM_015599.3

Inheritance

ClinVar variants

P:65U:176B:184

Top phenotype

Immunodeficiency 23

gnomAD constraint

pLI —, LoF o/e 0.42

Max pathogenic AF

—

Genomic locus

chr6:83,147,324-83,193,936

External References & Databases

Ensembl (ENSG00000013375)

Transcript & Mutation Effects

hg38 • Region Span ~46.6 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

immunodeficiency 23STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014353

Submitter: Labcorp Genetics (formerly Invitae)

immunodeficiency 23DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014353

Submitter: G2P

immunodeficiency 23STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014353

Submitter: PanelApp Australia

immunodeficiency 23SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014353

Submitter: Orphanet

immunodeficiency 23DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014353

Submitter: ClinGen

PGM3 was first reported in relation to autosomal receive immunodeficiency 23 in 1987 (Bjorksten B & Lundmar KM et al., PMID: 1245758; summarized by Zhang et al., 2014, 24589341). Immunodeficiency 23 is a rare congenital disorder of glycosylation caused by mutations in the PGM3 gene and characterized by neonatal to childhood onset of recurrent bacterial and viral infections, inflammatory skin diseases, atopic dermatitis and atopic diatheses, and marked serum IgE elevation. Early neurologic impairment is evident including developmental delay, intellectual disability, ataxia, dysarthria, sensorineural hearing loss, myoclonus and seizures. PGM3 encodes a member of the phosphohexose mutase family. The encoded protein mediates both glycogen formation and utilization by catalyzing the interconversion of glucose-1-phosphate and glucose-6-phosphate. (O'Leary NA et al., 2016, PMID: 26553804) Twelve variants (9 missense, 1 in-frame deletion, 1 frame-shift and 1 duplication) that have been reported in approximately 8 probands in 4 publications (Zhang Y, et al., 2014, PMID: 24589341; Sassi A, et al., 2014, PMID: 24698316; Lundin KE, et al., 2015, PMID: 26482871; Stray-Pedersen A et al., 2014 PMID: 24931394;), are included in this curation. The mechanism of disease for Immunodeficiency 23 is gene mutations result in the production of an enzyme with reduced activity. This gene-disease relationship is also supported by experimental evidence including expression of enzymatic activity in mouse models (Greig KT, et al., 2007, PMID: 17548465). In summary, there is strong evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Congenital Disorder of Glycosylation Expert Panel on the meeting date 9/20/2023 (SOP Version 9).

Clinical Genomic Database (CGD)

Immunodeficiency 23AR

Manifestation: Allergy/Immunology/Infectious; Audiologic/Otolaryngologic; Craniofacial; Musculoskeletal; Neurologic; Oncologic

Intervention: Allergy/Immunology/Infectious; Oncologic

Rationale: Individuals are susceptible to recurrent and severe viral, bacterial, and fungal infections (as well as sequelae such as EBV-related lymphoma), and and prophylaxis, as well as prompt and aggressive treatment of infections may be beneficial

Refs: 14981714; 24589341; 24698316; 24931394

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PGM3 variants in ClinVar

8 Conditions Cataloged

Immunodeficiency 23Total: 549

Inborn genetic diseasesTotal: 62

not specifiedTotal: 42

not providedTotal: 38

PGM3-related disorderTotal: 21

Severe combined immunodeficiency diseaseTotal: 12

Hyper-IgE syndromeTotal: 3

Fetal anomalies with a likely genetic causeTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_015599.3. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			2 clinvar	171 clinvar	1 clinvar	174
missense	5 clinvar	5 clinvar	170 clinvar	11 clinvar	1 clinvar	192
nonsense	8 clinvar	5 clinvar	2 clinvar			15
start loss						0
frameshift	26 clinvar	8 clinvar	1 clinvar			35
splice donor/acceptor (+/-2bp)		8 clinvar	1 clinvar			9
Total	39	26	176	182	2	425

Highest pathogenic variant AF is 0.00002788187

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 81 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_015599.3	RefSeq	NP_056414.1	12	MANE Select
ENST00000513973.6	Ensembl	ENSP00000424874.1	12	MANE Select
NM_001199917.2	RefSeq	NP_001186846.1	13	Standard
NM_001199918.2	RefSeq	NP_001186847.1	11	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

UDP-<i>N</i>-acetyl-D-galactosamine biosynthesis II
Amino sugar and nucleotide sugar metabolism - Homo sapiens (human)
Sialuria or French Type Sialuria
Sialuria or French Type Sialuria
Amino Sugar Metabolism

Biological Process

carbohydrate metabolic process
glucosamine metabolic process
UDP-N-acetylglucosamine biosynthetic process
protein N-linked glycosylation
protein O-linked glycosylation

Molecular Function

magnesium ion binding
phosphoacetylglucosamine mutase activity
phosphoglucomutase activity

Cellular Component

cellular_component
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000506587
Coding exons: 13
Length: 32787
Individuals with no LoFs: 125694
Homozygous LoFs: 0
Heterozygous LoFs: 54
Defined: 125748
p: 0.000215

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.51	227	301	0.755	0.0000144	3718
Missense (PolyPhen)		64	123.77	0.51707		1499
Synonymous	0.356	103	108	0.956	0.00000543	1087
Loss of Function	3.12	14	33.5	0.418	0.00000179	387

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00012	0.00012	rare
Latino/Admixed American	0.00018	0.00017	rare
Ashkenazi Jewish	0.00030	0.00030	rare
East Asian	0.00011	0.00011	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.00025	0.00025	rare
South Asian	0.00049	0.00039	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Catalyzes the conversion of GlcNAc-6-P into GlcNAc-1-P during the synthesis of uridine diphosphate/UDP-GlcNAc, a sugar nucleotide critical to multiple glycosylation pathways including protein N- and O-glycosylation. {ECO:0000303|PubMed:24589341, ECO:0000303|PubMed:24698316, ECO:0000303|PubMed:24931394}.;

Recessive Scores

pRec: 0.671

Intolerance Scores

LoFtool: 0.794
RVIS EVS: -0.27
RVIS percentile EVS: 34.6

Essentials

Essential (CRISPR): E
Essential (CRISPR2): E
Essential (gene trap): E
Indispensability pred.: N
Indispensability score: 0.136

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium