PYGM

Chr 11AR

glycogen phosphorylase, muscle associated

Also known as: GSD5

NCBI Gene: 5837 ENSG00000068976 UniProt: P11217 OMIM: 608455

The protein is a muscle enzyme that breaks down glycogen to glucose-1-phosphate during glycogenolysis. Mutations cause McArdle disease (glycogen storage disease type V), an autosomal recessive disorder characterized by exercise intolerance, muscle cramps, and myoglobinuria due to impaired muscle glycogen breakdown. The pathogenic mechanism involves gain-of-function mutations that disrupt normal glycogenolytic metabolism in skeletal muscle.

OMIM ResearchSummary from RefSeq, OMIM, Mechanism

This gene encodes a muscle enzyme involved in glycogenolysis. Highly similar enzymes encoded by different genes are found in liver and brain. Mutations in this gene are associated with McArdle disease (myophosphorylase deficiency), a glycogen storage disease of muscle. Alternative splicing results in multiple transcript variants.[provided by RefSeq, Sep 2009]

OMIM ResearchGenerating clinical summary…

MultiplemechanismARLOEUF 0.871 OMIM phenotype

Clinical Summary— PYGM

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Gene-Disease Validity (ClinGen)

glycogen storage disease V · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.87LOEUF

pLI 0.000

Z-score 2.22

OE 0.63 (0.47–0.87)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.05Z-score

OE missense 0.99 (0.92–1.07)

519 obs / 522.0 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.63 (0.47–0.87)

0≤0.351.4

Missense OE?0.99 (0.92–1.07)

0≤0.61.4

Synonymous OE?1.05

0≤1.21.6

LoF obs/exp: 27 / 42.6Missense obs/exp: 519 / 522.0Syn Z: -0.52

This gene — mechanism propensity

0.6938th %ile

GOF

0.7029th %ile

LOF

0.2970th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.