rs396514912 — OBSCN Protein-truncating variant

OBSCN Frameshift and Recurrent Rhabdomyolysis

Obscurin — encoded by OBSCN on chromosome 1q42 — is one of the largest proteins in the human body, a giant sarcomeric scaffold of nearly 800 kDa expressed in both cardiac and skeletal muscle. At the M-band and Z-disks of each sarcomere, obscurin tethers the sarcoplasmic reticulum to the myofibrils¹¹ obscurin tethers the sarcoplasmic reticulum to the myofibrils
Obscurin coordinates myofibrillogenesis, SR anchorage, and calcium homeostasis during contraction. Protein-truncating variants in OBSCN create a premature stop codon early in the transcript, eliminating the protein's C-terminal kinase and RhoGEF domains and stripping the SR of its structural anchor. When both copies of OBSCN carry such a truncation — homozygous or compound heterozygous — the resulting obscurin deficiency leaves skeletal muscle fibers highly vulnerable to injury from exertion or fever.

The Mechanism

This protein-truncating frameshift (c.708del, p.Ala237fs) removes a cytosine from an early coding exon, creating a frameshift that triggers nonsense-mediated decay of the transcript and eliminates full-length obscurin protein from muscle. Patient muscle biopsies from individuals with bi-allelic OBSCN loss show greatly reduced obscurin isoforms by Western blot²² Patient muscle biopsies from individuals with bi-allelic OBSCN loss show greatly reduced obscurin isoforms by Western blot
Reduction confirmed in 2 of 6 patients in Cabrera-Serrano 2022; consistent with NMD of the truncated transcript. Without obscurin, the sarcoplasmic reticulum loses its structural coupling to the sarcomere. In cultured myoblasts from affected individuals, the SR pumps calcium back more slowly under metabolic stress, suggesting impaired SERCA2a function or SR membrane integrity. This predisposes muscle fibers to cytotoxic calcium overload and membrane rupture — the cellular events underlying rhabdomyolysis. The disease follows a strict autosomal recessive pattern: heterozygous carriers in population databases and published cohorts do not show rhabdomyolysis, and monoallelic OBSCN truncation is not sufficient to produce this phenotype.

The Evidence

The pivotal study by Cabrera-Serrano et al. 2022³³ Cabrera-Serrano et al. 2022
Brain, 145(11):3985–3998, n=6 unrelated patients identified 10 bi-allelic loss-of-function OBSCN variants in 6 patients presenting with recurrent severe rhabdomyolysis. Onset was in the teenage years (ages 12–27 at first episode). Triggers included exercise (4 patients), heat (2 patients), prolonged travel (1 patient), and spontaneous episodes. Creatine kinase values during episodes reached 10,000–80,000 U/L, far above the clinical threshold for rhabdomyolysis (>5× ULN, ~1,000 U/L). None of the six patients had cardiomyopathy on echocardiography, distinguishing this biallelic skeletal muscle phenotype from the monoallelic HCM risk described in other OBSCN studies.

A subsequent case series by Zemorshidi et al. 2024⁴⁴ Zemorshidi et al. 2024
Neuromuscular Disorders, 34(1):42–47 described two additional patients with novel OBSCN protein-truncating variants presenting with muscle cramps, exercise intolerance, myoglobinuria, and rhabdomyolysis without cardiac involvement, expanding the genotypic breadth of the condition.

The specific frameshift variant captured by this locus (c.708del, ClinVar VCV003772679) is classified pathogenic by a neuromuscular genetics center, with an allele frequency of approximately 0.0001 (1 in 10,000) in gnomAD — consistent with the expected carrier frequency for a rare autosomal recessive disorder. No homozygotes appear in gnomAD, as expected for a severe pediatric/adolescent-onset condition.

Practical Implications

The key clinical action for bi-allelic carriers is trigger avoidance combined with an emergency response protocol for suspected episodes. Rhabdomyolysis in OBSCN-deficient individuals tends to be severe; CK values in published cases commonly exceed 30,000 U/L and can reach 80,000 U/L or higher, risking acute kidney injury. Intravenous fluid resuscitation (urine alkalinization, aggressive hydration) is the cornerstone of acute management and should be initiated early. Genetic counseling for affected individuals and their first-degree relatives is important: parents are obligate heterozygous carriers with no elevated rhabdomyolysis risk themselves.

Interactions

The monoallelic cardiac risk of OBSCN truncating variants — association with HCM in heterozygous carriers (rs71180793 and the OBSCN truncating variant class, OR 3.58 in Wu et al. 2021) — is a distinct phenotype from the biallelic skeletal rhabdomyolysis described here. Heterozygous carriers of this specific frameshift have no documented rhabdomyolysis risk based on current evidence.