rs1421405659 — MYBPC1 Leu259Pro

Ultra-rare dominant missense variant in slow skeletal myosin-binding protein C that disrupts sarcomere structure, causing early-onset myopathy with myogenic tremor (MYOTREM) and, in some families, distal arthrogryposis.

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When the Sarcomere Shakes: MYBPC1 and Myogenic Tremor

Most tremors originate in the brain or spinal cord — a glitch in neural circuitry. But heterozygous variants in MYBPC1, which encodes the slow-twitch isoform of myosin-binding protein C11 myosin-binding protein C
a structural protein in the C-zone of skeletal muscle sarcomeres that regulates actomyosin cross-bridge cycling, produce a tremor that arises from the muscle itself. This condition, now formally named MYOTREM (Myopathy, Congenital, with Tremor)22 MYOTREM (Myopathy, Congenital, with Tremor)
OMIM 618524; autosomal dominant, caused by heterozygous missense mutations in MYBPC1, combines mild to moderate skeletal muscle weakness with a characteristic involuntary muscle contraction at 10–11 Hz, present from early infancy.

rs1421405659 introduces a leucine-to-proline substitution at residue 259 of the slow MyBP-C protein (p.Leu259Pro). ClinVar classifies it as Likely Pathogenic / Pathogenic across three independent submissions. A second rare allele at this same codon (T>G, p.Leu259Arg) has also been reported; both alter the same leucine residue in the conserved M-motif of the protein. The variant is absent from gnomAD population databases, consistent with strong negative selection against dominant pathogenic variants at this locus.

The Mechanism

MYBPC1 encodes slow MyBP-C, a large (~150 kDa) modular protein located at 43-nm intervals along the thick filament backbone in slow (type I) skeletal muscle fibers. Its M-motif region — the region where pathogenic variants including Leu259Pro cluster — regulates how tightly myosin heads are held in a "super-relaxed" parked state between contractions. Stavusis et al. 201933 Stavusis et al. 2019
Ann Neurol 86:129-142. Two MYBPC1 M-motif mutations showed approximately 3.5× increased myosin-binding affinity in biochemical assays demonstrated that pathogenic M-motif missense variants increase myosin-binding affinity by approximately 3.5-fold, preventing myosin heads from fully returning to the super-relaxed state between contractions. This persistent partial activation produces asynchronous, repetitive sarcomere contractions — the cellular basis of the 10–11 Hz myogenic tremor44 myogenic tremor
tremor originating from within the muscle itself, not from neurological dysfunction.

Unlike cardiac MYBPC3 pathogenic variants, which disrupt myosin-head parking in the heart and cause hypertrophic cardiomyopathy, MYBPC1 Leu259Pro primarily affects slow skeletal fibers. Cardiac muscle is spared because the cardiac isoform is encoded by a different gene (MYBPC3, chr11q11).

The Evidence

Geist Hauserman et al. 202155 Geist Hauserman et al. 2021
JCI Insight. Characterized sarcomeric deficits in MYBPC1-associated myopathy; cohort of patients from multiple families with dominant missense variants systematically described the MYOTREM phenotype: generalized muscle weakness, hypotonia, dysmorphia, skeletal deformities (scoliosis, chest wall abnormalities, hip dysplasia), and the defining myogenic tremor. EMG studies in affected individuals show myopathic changes alongside spontaneous rhythmic discharges consistent with sarcomeric instability rather than denervation.

Lanvin et al. 202466 Lanvin et al. 2024
Neurol Clin Pract 14(3). Three additional pediatric patients from two families; broadened spectrum to include neonatal respiratory distress requiring noninvasive ventilation and stridor expanded the recognized phenotype to include severe neonatal respiratory compromise, highlighting that diaphragm and intercostal slow-fiber involvement can be life-threatening in the newborn period. The authors note that "tremors and respiratory distress associated with stridor should raise the diagnosis of congenital myopathy with tremors linked to MYBPC1-dominant variants in children with neonatal hypotonia."

Muscle biopsy in MYOTREM patients typically shows predominance of type I (slow) fibers with variable fiber-size disproportion, consistent with the slow-fiber-specific expression of MYBPC1. Type II fast fibers, which express MYBPC2 rather than MYBPC1, are relatively preserved.

Practical Actions

Carriers of a pathogenic MYBPC1 variant should pursue proactive neuromuscular and respiratory surveillance. The tremor is myogenic, not neurological — this means beta-blockers and other tremor medications targeting the central nervous system are unlikely to be effective, and the management focus should be on supportive myopathy care.

Respiratory involvement is the most clinically urgent concern, particularly in infancy. Annual pulmonary function testing (spirometry and forced vital capacity) is recommended once a child can cooperate, with nocturnal oximetry to screen for hypoventilation. If scoliosis develops — common in MYOTREM — spinal curvature monitoring becomes especially important as it compounds respiratory compromise.

Physiotherapy targeting slow-fiber-dominant muscles (postural muscles, hip girdle, respiratory musculature) may preserve function, but no disease-modifying pharmacotherapy currently exists. Creatine supplementation has shown modest benefit in some congenital myopathies with thin-filament involvement, though no MYBPC1-specific trials have been conducted.

Interactions

rs1421405659 (MYBPC1 Leu259Pro) is a dominant variant that acts independently — a single copy is sufficient for full clinical expression. There is no documented interaction with common modifier variants that substantially alters penetrance in published literature. However, the distal arthrogryposis phenotype (OMIM 614335) seen with MYBPC1 variants including W236R and Y856H (Gurnett et al. 201077 Gurnett et al. 2010
Hum Mol Genet 19(8):1462-70. First identification of MYBPC1 in DA1) may be influenced by fetal movement patterns during development, where overlapping variants affecting other sarcomeric proteins could modulate joint contracture severity.

Family screening is critical: first-degree relatives of an identified carrier have a 50% risk of inheriting the pathogenic allele. Relatives with unexplained muscle weakness, lifelong tremor, or contractures in childhood should be prioritized for genetic evaluation.

Genotype Interpretations

What each possible genotype means for this variant.

TT Non-carrier Normal

No MYBPC1 Leu259Pro variant detected; standard slow-fiber sarcomere structure

You carry two copies of the reference T allele at rs1421405659. Your slow MyBP-C protein functions normally at position 259, maintaining appropriate myosin head parking and sarcomere regulation in slow-twitch skeletal muscle. The pathogenic Leu259Pro substitution is not present in your genome at this locus. This is the genotype present in essentially all individuals in population databases — the C allele is absent from gnomAD across all major ancestry groups, reflecting its rarity and the strong disease association.

CT Pathogenic Carrier High Risk

Heterozygous for MYBPC1 Leu259Pro — likely pathogenic variant for MYOTREM and early-onset myopathy

The p.Leu259Pro substitution disrupts the M-motif, a conserved regulatory region of MyBP-C responsible for controlling myosin-head super-relaxation. In unaffected individuals, slow MyBP-C holds myosin heads in a parked state between contractions, preventing futile cross-bridge cycling. Leu259Pro increases myosin-binding affinity by approximately 3.5-fold (measured for related M-motif variants E248K and Y247H in Stavusis et al. 2019), preventing complete disengagement. The resulting asynchronous thin-filament activation at 10–11 Hz produces the characteristic myogenic tremor.

Muscle biopsy typically shows type I fiber predominance with variable fiber-size disproportion and, in some cases, nemaline rods or other thin-filament pathology. Serum CK may be mildly elevated. EMG reveals myopathic features with spontaneous rhythmic discharges. Cardiac involvement has not been reported for MYBPC1 variants, as cardiac muscle expresses the distinct MYBPC3 isoform.

Phenotypic variability exists even within families sharing the same mutation: some heterozygotes have pronounced weakness and scoliosis, while others have only mild tremor. Age of diagnosis ranges from neonatal (with respiratory failure) to childhood (with motor delay and tremor noticed at school age). Sex-dependent progression has been observed in mouse models of related MYBPC1 variants (Mariano et al. 2025, PMID 40569690), suggesting biological sex may modulate clinical severity.

CC Homozygous Homozygous

Homozygous for MYBPC1 Leu259Pro — both copies of slow MyBP-C are disrupted; severe congenital myopathy expected

You carry two copies of the pathogenic C allele (p.Leu259Pro). This genotype has not been described in published literature — all reported MYOTREM cases are heterozygous — but by analogy with other dominant sarcomeric myopathy genes, homozygosity would be expected to produce a severely affected phenotype, likely with marked neonatal hypotonia, respiratory failure, and profound weakness. The complete absence of functional slow MyBP-C from type I muscle fibers would remove all super-relaxation braking of myosin cross-bridge cycling. If this result is correct and not a technical artifact, urgent evaluation by a neuromuscular disease specialist is warranted. Technical verification (repeat testing from a fresh sample) is recommended before drawing clinical conclusions.