rs119103258 — PYGM

PYGM Trp798Arg — When a Missense Mutation Erases a Protein

Most genetic diseases work by a familiar logic: if you change a gene's sequence, you change its protein. But the PYGM Trp798Arg mutation (also written W798R or c.2392T>C) tells a stranger story. Patients who carry this variant produce normal amounts of PYGM messenger RNA — the gene is being read and copied faithfully — yet their muscle cells contain virtually no myophosphorylase¹¹ myophosphorylase
muscle-specific glycogen phosphorylase, the enzyme encoded by PYGM that cleaves glucose-1-phosphate from glycogen at the start of exercise protein. The mutation seems to hijack a post-translational quality-control system, condemning the newly made protein to rapid degradation before it can fold and function. The result is a complete block in muscle glycogenolysis indistinguishable from a frameshift or nonsense variant.

This is McArdle disease²² McArdle disease
glycogen storage disease type V (GSD-V), an autosomal recessive metabolic myopathy first described by Brian McArdle in 1951 and caused by loss of functional myophosphorylase in skeletal muscle: exercise intolerance, painful cramps in the first minutes of exertion, and the characteristic "second wind" as blood-glucose and fatty-acid delivery eventually compensate for the absent glycogenolytic pathway.

ClinVar classifies Trp798Arg as Pathogenic³³ ClinVar classifies Trp798Arg as Pathogenic
VCV000002312, criteria provided, multiple submitters, no conflicts for glycogen storage disease type V, with eleven contributing submissions.

The Mechanism

Tryptophan 798 sits in the C-terminal catalytic domain of myophosphorylase, near the region involved in dimer interface contacts and allosteric effector binding. The substitution of tryptophan (neutral, aromatic, bulky) with arginine (positively charged, flexible) creates a physicochemical mismatch that the cell's protein quality control system apparently cannot tolerate.

The critical evidence comes from an iPSC-based skeletal muscle model developed by Lucía et al.⁴⁴ Lucía et al.
Lucía A et al. Creation of an iPSC-based skeletal muscle model of McArdle disease harbouring the mutation c.2392T>C (p.Trp798Arg) in the PYGM gene. Biomedicines, 2023. Patient-derived myofibers showed: (1) PYGM mRNA expression statistically indistinguishable from healthy controls; (2) complete absence of myophosphorylase protein by Western blot and immunofluorescence; and (3) PAS-positive glycogen accumulation around cell nuclei — the morphological signature of McArdle disease. The mRNA-protein discordance points to a post-translational mechanism: the mutant protein is produced but immediately recognized as misfolded and degraded, likely by the proteasomal or chaperone-mediated quality-control machinery.

This "unexpected consequence" of a missense mutation has been observed broadly across PYGM pathogenic missense variants — many of which cause complete myophosphorylase absence despite their theoretical missense status. The clinical implication is that Trp798Arg homozygotes and compound heterozygotes have the same functional deficit as patients carrying nonsense or frameshift mutations: zero functional enzyme.

The Evidence

The variant was identified as a recurrent allele in the Spanish McArdle population by Rubio et al.⁵⁵ Rubio et al.
Rubio JC et al. A proposed molecular diagnostic flowchart for myophosphorylase deficiency (McArdle disease) in blood samples from Spanish patients. Hum Mutat, 2007, who found it in 9 of 55 Spanish patients — making it the third most frequent PYGM mutation in Spain alongside p.R50X and p.Gly205Ser, and characterizing it as "a virtually Spanish-private mutation" not identified in British, American, German, French, or Italian cohorts.

A 2015 comprehensive update of all documented PYGM mutations by Nogales-Gadea et al.⁶⁶ Nogales-Gadea et al.
Nogales-Gadea G et al. McArdle disease: update of reported mutations and polymorphisms in the PYGM gene. Hum Mutat, 2015 catalogued 147 pathogenic mutations. Trp798Arg is documented as the second most frequent pathogenic missense allele in the Spanish population, with no genotype-phenotype correlation found across PYGM variants — the specific mutation does not predict disease severity.

Vieitez et al.⁷⁷ Vieitez et al.
Vieitez I et al. Molecular and clinical study of McArdle's disease in a cohort of 123 European patients. Neuromuscul Disord, 2011 confirmed the dominance of p.R50X (61.7% allelic frequency) across European populations and the population-specific distribution of secondary alleles, with no cross-population case of Trp798Arg in non-Spanish Europeans.

McArdle disease affects approximately 1 in 100,000–167,000 people globally. Life expectancy is normal; about 11% of patients develop permanent proximal weakness after age 40, and rhabdomyolysis episodes carry acute kidney injury risk.

Practical Actions

The management of McArdle disease is identical regardless of which specific PYGM pathogenic mutation is present — phenotype tracks with enzyme absence, not genotype. The most validated, genotype-specific interventions are:

Pre-exercise sucrose: 25–40 g of sucrose 5 minutes before exercise significantly improves tolerance by raising blood glucose before glycolysis demand peaks. This is the most validated nutritional intervention specific to myophosphorylase deficiency — it bypasses the glycogen block by providing circulating glucose directly.

Second-wind strategy: Starting exercise at very low intensity for 8–10 minutes allows blood-glucose delivery and fatty acid mobilization to compensate for the absent glycogenolytic pathway before effort is increased. Patients who exploit this phenomenon achieve substantially better exercise capacity.

Myoglobinuria recognition: Dark urine after exertion signals rhabdomyolysis and requires immediate rest, aggressive hydration, and emergency evaluation for acute kidney injury.

Interactions

This is an autosomal recessive variant. Compound heterozygosity — inheriting Trp798Arg on one chromosome and any other pathogenic PYGM allele (R50X, Gly205Ser, or any of the ~147 documented variants) on the other — produces full McArdle disease with zero functional myophosphorylase. The most common pairings in Spanish patients involve compound heterozygosity between Trp798Arg and p.R50X (rs116855232).

The "virtually Spanish-private" epidemiology of Trp798Arg means this allele is of greatest clinical relevance in patients of Iberian or Latin American descent. Genetic panels for McArdle disease in Spanish-ancestry individuals should explicitly include this variant alongside R50X and Gly205Ser.