rs267606993 — PYGM PYGM Met1Val (start-loss)

PYGM Met1Val — The Muscle Glycogen Lock

Every time you climb stairs, sprint for a bus, or carry groceries, your muscle cells burn through their internal glycogen stores in the first few seconds of exertion. The enzyme responsible for unlocking those stores is myophosphorylase¹¹ myophosphorylase
muscle-specific glycogen phosphorylase, encoded by PYGM on chromosome 11q13 — and in McArdle disease, it doesn't work. Glycogen accumulates unused inside muscle fibers while the cells starve for the glucose they need.

The rs267606993 variant (c.1A>G, p.Met1Val) eliminates the start codon of PYGM entirely. The coding sequence begins with ATG — methionine — and the A>G substitution on the coding strand converts that to GTG (valine). In theory this creates a missense change, but in practice the next available in-frame methionine is at codon 92, meaning any protein produced from the alternate start site is severely truncated and non-functional. The gene effectively produces nothing useful. ClinVar classifies this variant²² ClinVar classifies this variant
ClinVar VCV000002309, pathogenic, multiple submitters no conflicts as pathogenic for glycogen storage disease type V (GSD-V, McArdle disease).

The Mechanism

In healthy muscle, glycogen phosphorylase cleaves glucose-1-phosphate from glycogen chains at the start of exercise, feeding glycolysis to produce ATP. This process is especially critical in the first 8–10 minutes of sustained exertion, before fatty acid oxidation and increased cardiac output can meet energy demand. Without myophosphorylase, muscle cells cannot access their glycogen reserve at all. They rely entirely on blood glucose and fatty acids from the start of exercise — supplies that arrive too slowly in early exertion, producing the characteristic cramping and weakness of McArdle disease.

The "second wind" phenomenon — one of the most distinctive features of McArdle disease — reflects this metabolic bottleneck: after 8–10 minutes of moderate activity, blood glucose delivery, fat mobilization, and heart rate adaptation catch up, and exercise becomes much more tolerable. Patients who learn to pace themselves through the initial difficulty often exercise reasonably well once the second wind arrives.

The Evidence

The Met1Val variant was first identified by Vorgerd et al.³³ Vorgerd et al.
Vorgerd M et al. Mutation analysis in myophosphorylase deficiency (McArdle's disease). Ann Neurol, 1998 in a homozygous Turkish patient. The same research confirmed that R50X (p.Arg50*) is the dominant PYGM mutation in European white populations (allelic frequency ~60%), while start-codon and other loss-of-function variants account for a smaller but well-documented share of cases.

A larger European cohort study by Vieitez et al.⁴⁴ 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 identified 20 novel PYGM mutations across 123 patients and found no genotype-phenotype correlation — the specific PYGM mutation carried does not predict disease severity. This means a patient with Met1Val can have mild or severe disease independent of which variant they carry.

The Met1Val variant emerged as the most prevalent PYGM mutation in Turkish patients in a study by Inal-Gültekin et al.⁵⁵ Inal-Gültekin et al.
Inal-Gültekin G et al. Myophosphorylase (PYGM) mutations determined by next generation sequencing in a cohort from Turkey with McArdle disease. Neuromuscul Disord, 2017, found in 27 of 67 patients across 11 families, illustrating the population-specific distribution of PYGM alleles.

McArdle disease affects approximately 1 in 100,000–170,000 people globally. Life expectancy is normal, though about 11% of patients develop permanent proximal weakness after age 40 and half experience episodes of myoglobinuria that can threaten kidney function if severe.

Practical Actions

The key interventions for McArdle disease are specific to myophosphorylase deficiency and would not be recommended to anyone without a genetic test:

Pre-exercise sucrose: Consuming 25–40 g of sucrose (a glass of orange juice, a banana, or a sports drink) 5 minutes before exercise significantly improves exercise tolerance by elevating blood glucose before myophosphorylase is needed. This is the single most validated pharmacological/nutritional intervention in McArdle disease, specific to the metabolic block.

The warm-up strategy: Starting exercise at very low intensity for 10 minutes allows the second wind to arrive before high-intensity effort begins. Patients trained in this strategy show dramatically reduced exercise-related cramps and myoglobinuria risk compared to sudden high-intensity bursts.

Myoglobinuria recognition: Dark, cola-colored urine after exercise signals rhabdomyolysis — acute muscle breakdown releasing myoglobin, which is filtered by the kidneys. Any episode requires immediate rest, high fluid intake, and medical evaluation; severe episodes cause acute kidney injury.

Regular aerobic exercise: Supervised aerobic training (starting at 30% of VO2max, increasing gradually) improves mitochondrial capacity and thus reduces dependence on early glycogenolysis. This is a genotype-specific rationale for structured aerobic conditioning that would not be recommended to unaffected individuals.

Interactions

This is an autosomal recessive variant. Compound heterozygosity — inheriting Met1Val on one chromosome and a different pathogenic PYGM variant (such as R50X, Gly205Ser, or any of the ~180 known pathogenic alleles) on the other — produces full McArdle disease phenotype equivalent to homozygosity. The diagnostic implication for carriers is primarily reproductive: if both parents carry any pathogenic PYGM variant, each child has a 25% chance of inheriting biallelic loss-of-function alleles and developing GSD-V.

Note on multi-allelic representation: rs267606993 is a multi-allelic site at the PYGM start codon with three pathogenic alternate alleles on the plus strand (T>A = p.Met1Leu; T>C = p.Met1Val; T>G = p.Met1Leu via different codon). This entry represents the T>C (Met1Val) variant as the primary risk allele (C), consistent with ClinVar VCV000002309. The other two alternates (ClinVar 553271, 156341) have identical clinical significance and are captured under the same rsID.