rs396514912 — OBSCN Protein-truncating variant

Protein-truncating frameshift deletion in obscurin; homozygous or compound heterozygous carriers lose functional obscurin in muscle, predisposing to recurrent, exercise-triggered rhabdomyolysis.

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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.

Genotype Interpretations

What each possible genotype means for this variant.

II Non-Carrier Normal

No OBSCN frameshift detected — no rhabdomyolysis risk from this variant

You carry two intact copies of the OBSCN gene at this position. This is the overwhelmingly common genotype — fewer than 1 in 5,000 people carry even one copy of this frameshift deletion. You have no elevated risk of OBSCN-related rhabdomyolysis from this variant.

DI Carrier Carrier

Heterozygous carrier — one copy of OBSCN frameshift, no personal rhabdomyolysis risk

Rhabdomyolysis susceptibility 1 (RHABDO1, OMIM 620235) requires biallelic (homozygous or compound heterozygous) loss-of-function in OBSCN. Cabrera-Serrano et al. 2022 (PMID 34957489) specifically noted that obligate carrier parents of affected patients did not have rhabdomyolysis, confirming autosomal recessive inheritance. The carrier frequency of this specific frameshift is approximately 0.01% (1 in 10,000) in gnomAD — rare enough that compound heterozygosity is uncommon in the general population.

For the cardiac phenotype, Wu et al. 2021 (PMID 34601892) found OBSCN truncating variants enriched 3.4-fold in HCM patients (2.6% of cases vs. 0.8% of controls) with OR 3.58 at replication. This risk applies to heterozygous OBSCN truncating variant carriers in general. Discuss cardiac screening with your physician based on personal and family history.

DD Homozygous Homozygous

Homozygous for OBSCN frameshift — high rhabdomyolysis susceptibility, requires medical management

Bi-allelic OBSCN protein-truncating variants eliminate functional obscurin protein from skeletal muscle, compromising sarcoplasmic reticulum structural coupling and calcium homeostasis. Patient myoblasts show impaired SR calcium reuptake under stress (Cabrera- Serrano et al. 2022, PMID 34957489), leaving muscle fibers highly susceptible to exercise-induced cytotoxic calcium overload. Published cases (n=8 across two cohorts) present with: onset age 12–27 years, exercise-triggered or spontaneous CK elevations

10,000 U/L (range 10,000–80,000 U/L), myalgia, cramps, and myoglobinuria. Acute kidney injury is a serious complication of severe episodes. None of the published patients developed cardiomyopathy, distinguishing this from the monoallelic cardiac OBSCN phenotype.

Avoid strenuous exercise, prolonged immobilization, high fever, and other known triggers. A written emergency protocol including early IV hydration is advisable. Inform all healthcare providers of this diagnosis before any general anesthesia or strenuous medical procedure.