PGM1

protein-coding

phosphoglucomutase 1

Gene summary

The protein encoded by this gene is an isozyme of phosphoglucomutase (PGM) and belongs to the phosphohexose mutase family. There are several PGM isozymes, which are encoded by different genes and catalyze the transfer of phosphate between the 1 and 6 positions of glucose. In most cell types, this PGM isozyme is predominant, representing about 90% of total PGM activity. In red cells, PGM2 is a major isozyme. This gene is highly polymorphic. Mutations in this gene cause glycogen storage disease type 14. Alternativley spliced transcript variants encoding different isoforms have been identified in this gene.[provided by RefSeq, Mar 2010]

MANE transcript

NM_002633.3

Inheritance

ClinVar variants

P:54U:188B:129

Top phenotype

Congenital disorder of glycosylation, type It

gnomAD constraint

pLI —, LoF o/e 0.93

Max pathogenic AF

—

Genomic locus

chr1:63,593,411-63,660,245

External References & Databases

Ensembl (ENSG00000079739)

Transcript & Mutation Effects

hg38 • Region Span ~66.8 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

PGM1-congenital disorder of glycosylationSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013968

Submitter: PanelApp Australia

PGM1-congenital disorder of glycosylationDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013968

Submitter: ClinGen

The relationship between *PGM1* and PGM1-Congenital Disorder of Glycosylation (Congenital disorder of glycosylation, type It included), an autosomal recessive disorder, was evaluated using the ClinGen Clinical Validity Framework as of June, 2023. *PGM1* encodes phosphoglucomutase 1, the predominant PGM isoform in most cell types, contributing to 90% of total PGM activity, except red blood cells, wherein PGM2 is the major isoform, and the brain. Redundancy of PGM1 activity in the brain correlates well with the absence of neurological phenotypes in patients with PGM1 deficiency. The primary role of phosphoglucomutase 1 is to catalyze the interconversion of glucose 1-phosphate and glucose 6-phosphate, and it is involved in several crucial metabolic pathways including glycolysis, glycogenolysis, glycogenesis and N-linked glycosylation (PMID: 24499211, 28794993). The clinical manifestations of PGM1-congenital disorder of glycosylation (PGM1-CDG) include bifid uvula, myopathy, hepatopathy, short stature, hypoglycemia and dilated cardiomyopathy. *PGM1* was first reported in relation to autosomal recessive PGM1-CDG in 2009 (Stojkovic et al, 2009; PMID: 19625727). More than 30 nonsense, splice site, frameshift, deletion/duplication and missense variants have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Summary of Case Level Data (12 points): Variants in this gene have been reported in at least 8 probands in 2 publication (PMID: 19625727, 24499211). More evidence is available in the literature, but the maximum score for genetic evidence was reached. The mechanism for disease is biallelic loss of function. Summary of experimental data (6 points): This gene-disease relationship is supported by in vitro functional studies, model organisms and rescue evidence. The function of *PGM1* is well understood and the onset of symptoms is associated with defects in glycosylation, which can be rescued to an extent by supplementing with galactose (PMID: 24499211, 28794993). Constitutive knock-out of *Pgm2*, the mouse ortholog of human *PGM1*, leads to embryonic lethality (PMID: 31077402). Cardiomyocyte-specific conditional knock-out of *Pgm2* in mice recapitulates the human dilated cardiomyopathy phenotype seen in some patients with PGM1-CDG (PMID: 36709920). The defect in cKO mice is rescued when AAV-mediated WT *Pgm2* is introduced into the affected animals (PMID: 36709920). In summary, *PGM1* is definitively associated with autosomal recessive PGM1-CDG. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the Congenital Disorders of Glycosylation GCEP on August 2nd, 2023.

PGM1-congenital disorder of glycosylationSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013968

Submitter: Labcorp Genetics (formerly Invitae)

PGM1-congenital disorder of glycosylationSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013968

Submitter: Ambry Genetics

PGM1-congenital disorder of glycosylationSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013968

Submitter: Orphanet

PGM1-congenital disorder of glycosylationDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013968

Submitter: G2P

PGM1-congenital disorder of glycosylationSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013968

Submitter: Genomics England PanelApp

Clinical Genomic Database (CGD)

Congenital disorder of glycosylation, type ItAR

Manifestation: Biochemical; Cardiovascular; Endocrine; Gastrointestinal; Musculoskeletal; Neurologic; Renal

Intervention: Biochemical; Cardiovascular; Hematologic; Pharmacogenomic; Renal

Rationale: Treatment with galactose has been described as beneficial (including related to individuals with reported hypogonadotropic hypogonadism as well as parameters related to hepatic function); Individuals may have exercise-induced intolerance with episodic rhabdomyolysis, and precautions may decrease associated morbidity; Individuals have been described with dilated cardiomyopathy, and surveillance may allow early medical management; Awareness of coagulopathies may be beneficial in terms of medical management, especially in situations such as surgery; Hepatic-metabolized agents should be avoided; Cardiac transplant has been described

Refs: 19625727; 22492991; 24499211; 28617415

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PGM1 variants in ClinVar

8 Conditions Cataloged

PGM1-congenital disorder of glycosylationTotal: 340

not providedTotal: 130

Inborn genetic diseasesTotal: 79

not specifiedTotal: 51

PGM1-related disorderTotal: 46

Congenital disorder of glycosylationTotal: 1

Fetal anomalies with a likely genetic causeTotal: 1

Acute rhabdomyolysisTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_002633.3. 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			6 clinvar	120 clinvar		126
missense	4 clinvar	11 clinvar	174 clinvar	8 clinvar	1 clinvar	198
nonsense	7 clinvar	6 clinvar	1 clinvar			14
start loss						0
frameshift	19 clinvar	2 clinvar	1 clinvar			22
splice donor/acceptor (+/-2bp)	1 clinvar	4 clinvar	6 clinvar			11
Total	31	23	188	128	1	371

Highest pathogenic variant AF is 0.00011958091

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 35 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_002633.3	RefSeq	NP_002624.2	11	MANE Select
ENST00000371084.8	Ensembl	ENSP00000360125.3	11	MANE Select
NM_001172818.1	RefSeq	NP_001166289.1	11	Standard
NM_001172819.2	RefSeq	NP_001166290.1	8	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Glycolysis / Gluconeogenesis - Homo sapiens (human)
Starch and sucrose metabolism - Homo sapiens (human)
Purine metabolism - Homo sapiens (human)
Galactose metabolism - Homo sapiens (human)
Amino sugar and nucleotide sugar metabolism - Homo sapiens (human)

Biological Process

glycogen biosynthetic process
glycogen catabolic process
glucose metabolic process
gluconeogenesis
glycolytic process

Molecular Function

magnesium ion binding
phosphoglucomutase activity
protein binding

Cellular Component

extracellular region
cytoplasm
cytosol
actin cytoskeleton
extracellular exosome

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000371083
Coding exons: 11
Length: 66970
Individuals with no LoFs: 123485
Homozygous LoFs: 18
Heterozygous LoFs: 2245
Defined: 125748
p: 0.00904

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.228	336	324	1.04	0.0000196	3816
Missense (PolyPhen)		148	143.48	1.0315		1606
Synonymous	-1.36	139	120	1.16	0.00000732	1132
Loss of Function	0.317	23	24.7	0.931	0.00000140	305

Population LoF Frequency

Population	CAF	p-value	Status
African	0.0023	0.0020	notable
Latino/Admixed American	0.0029	0.0029	notable
Ashkenazi Jewish	0.021	0.020	notable
East Asian	0.00073	0.00071	rare
Finnish	0.0075	0.0073	notable
European (Non-Finnish)	0.015	0.014	notable
South Asian	0.0029	0.0028	notable
Other	0.0088	0.0085	notable

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: This enzyme participates in both the breakdown and synthesis of glucose.;
Disease: DISEASE: Congenital disorder of glycosylation 1T (CDG1T) [MIM:614921]: A form of congenital disorder of glycosylation, a multisystem disorder caused by a defect in glycoprotein biosynthesis and characterized by under-glycosylated serum glycoproteins. Congenital disorders of glycosylation result in a wide variety of clinical features, such as defects in the nervous system development, psychomotor retardation, dysmorphic features, hypotonia, coagulation disorders, and immunodeficiency. The broad spectrum of features reflects the critical role of N-glycoproteins during embryonic development, differentiation, and maintenance of cell functions. {ECO:0000269|PubMed:19625727, ECO:0000269|PubMed:22492991, ECO:0000269|PubMed:22976764, ECO:0000269|PubMed:24499211, ECO:0000269|PubMed:25288802, ECO:0000269|PubMed:26972339}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.631

Intolerance Scores

LoFtool: 0.803
RVIS EVS: -0.22
RVIS percentile EVS: 37.66

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.989

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	High	High	High
Primary Immunodeficiency	High	High	High
Cancer	High	High	High