rs187830361 — MYBPC3 Trp792Arg (W792R)

The C6 Domain Sentinel: MYBPC3 Trp792Arg and Hypertrophic Cardiomyopathy

MYBPC3¹¹ MYBPC3
myosin-binding protein C3, encoding the cardiac isoform of cMyBP-C — a 150 kDa structural protein in the thick filament C-zone of cardiomyocytes that regulates actomyosin cross-bridge cycling and myosin super-relaxation is the single most commonly mutated gene in familial hypertrophic cardiomyopathy (HCM), accounting for 40–50% of all genetically explained HCM cases. rs187830361 introduces a tryptophan-to-arginine substitution at codon 792 (p.Trp792Arg), sitting squarely in the C6 fibronectin type III²² fibronectin type III
a structural protein fold found in many extracellular matrix and sarcomeric proteins; in MYBPC3, FnIII domains form the modular "immunoglobulin-like" repeat scaffold that connects the protein to thick-filament myosin domain — one of three MYBPC3 sub-domains (C3, C6, C10) enriched for disease-causing missense mutations. ClinVar classifies the c.2374T>C (plus-strand A>G) change as Pathogenic/Likely pathogenic³³ Pathogenic/Likely pathogenic
VCV000036605; multiple submitters, no conflicts ★★; conditions include primary familial HCM, hypertrophic cardiomyopathy 4, and left ventricular noncompaction 10 across 11 independent submissions. The variant is absent or near-absent in gnomAD population databases, consistent with strong purifying selection against dominant cardiac disease alleles.

The Mechanism

Tryptophan 792 occupies a conserved hydrophobic core of the C6 FnIII domain. Replacing it with the bulkier, charged arginine residue disrupts the tight hydrophobic packing required for domain stability. Smelter et al. 2018⁴⁴ Smelter et al. 2018
Am J Physiol Heart Circ Physiol 314(6):H1179–H1191. Engineered cardiac tissue expressing W792R showed contractile kinetics nearly identical to cMyBP-C-deficient tissue, establishing functional haploinsufficiency as the pathogenic mechanism demonstrated that the W792R protein is expressed at substantially reduced levels despite normal mRNA abundance — the mutant protein folds abnormally and is degraded, leaving the cardiomyocyte functionally deficient in cMyBP-C from the mutant allele.

Unlike C10-domain missense variants (which fail to incorporate into myofilaments entirely), C6-domain W792R protein incorporates into the sarcomere at normal positions but disrupts the conformational dynamics that govern how cMyBP-C interacts with myosin heads and actin. Mertens et al. 2024⁵⁵ Mertens et al. 2024
J Mol Cell Cardiol 197:86-97. Homozygous W792R knock-in mice develop cardiac hypertrophy and fibrosis by postnatal day 10, lethal by day 21; heterozygotes show normal morphology, consistent with dominant-haploinsufficiency model showed in a mouse knock-in model that the mutation preferentially drives calcium-sensitizing interactions with actin rather than inhibitory interactions with myosin — the net result is increased basal contractility and the pathological remodeling characteristic of HCM.

Computational stability modeling⁶⁶ Computational stability modeling
STRUM algorithm; ΔΔG −1.28 kcal/mol for W792R; variants with ΔΔG ≤ −1.2 show HR 2.29 for adverse cardiac events independently predicts W792R as a destabilizing variant (ΔΔG −1.28 kcal/mol, just below the −1.2 kcal/mol clinical risk threshold), providing orthogonal support for pathogenicity beyond clinical case counts.

The Evidence

The W792R variant was established as pathogenic through a combination of functional characterization and clinical genetics. In the largest MYBPC3 cohort to date, Ho et al. 2021⁷⁷ Ho et al. 2021
Circ Genom Precis Med 14(1):e002929. SHaRe Registry; 1,316 patients with pathogenic MYBPC3 variants; nontruncating variants cluster in C3, C6, and C10 domains in 82% of cases; clinical outcomes equivalent between truncating and nontruncating carriers analyzed 1,316 MYBPC3 HCM patients from the Sarcomeric Human Cardiomyopathy Registry (SHaRe) and found that C6-domain nontruncating variants — the class to which W792R belongs — produce equivalent adverse event rates to truncating variants. This refutes the prior assumption that missense variants are less severe than truncating mutations.

MYBPC3 pathogenic variants as a class show age-dependent, incomplete penetrance⁸⁸ age-dependent, incomplete penetrance
penetrance 50% by age 36, 75% by age 40, approaching 100% by age 55 in most founder cohorts; sex-dependent — males typically develop HCM 10-20 years earlier than females with the same variant. Heterozygous carriers who are phenotype-negative (no LVH on echocardiogram) remain at risk throughout life — particularly during periods of physiological stress such as pregnancy, competitive athletics, or rapid blood pressure elevation.

Sudden cardiac death (SCD) risk in MYBPC3 HCM is estimated at approximately 2-fold above background HCM risk, particularly in younger carriers with marked LVH (maximum wall thickness ≥30 mm), exercise-induced syncope, or non-sustained ventricular tachycardia on Holter monitoring.

Practical Actions

Carriers of the W792R variant require proactive cardiac surveillance regardless of current symptoms. The 2024 AHA/ACC HCM guideline recommends comprehensive echocardiographic evaluation at initial diagnosis, with periodic repeat imaging⁹⁹ periodic repeat imaging
gene-positive phenotype-negative relatives: annually in adolescence, every 3-5 years in adulthood; more frequent if subclinical markers present (diastolic dysfunction, myocardial crypts, elongated mitral leaflets) even before any structural change appears. Because LVH may not manifest until the 4th or 5th decade, a normal baseline echo is not reassuring for life — follow-up is mandatory.

Competitive high-intensity sport carries elevated SCD risk in HCM carriers. A sports cardiology or HCM specialist should provide activity guidance before any athletic competition. Pharmacotherapy (beta-blockers, disopyramide) can reduce outflow obstruction; mavacamten¹⁰¹⁰ mavacamten
a cardiac myosin ATPase inhibitor approved 2022; first disease-specific drug for HCM; reduces LV outflow tract gradient and improves symptoms in obstructive HCM is now guideline-supported for symptomatic obstructive HCM. ICD implantation is considered when SCD risk calculators indicate ≥4-6% 5-year risk.

Interactions

MYBPC3 W792R follows autosomal dominant inheritance — a single pathogenic copy is sufficient for disease. Compound heterozygosity (inheriting one truncating and one missense MYBPC3 variant, or two MYBPC3 variants from different parental alleles) can produce a more severe phenotype, up to pediatric lethal cardiomyopathy. If a relative is found to carry a different MYBPC3 pathogenic variant, the proband should be tested for that variant as well to exclude compound heterozygosity. Interactions with MYH7¹¹¹¹ MYH7
beta-myosin heavy chain; second most common HCM gene; MYBPC3 + MYH7 double heterozygotes have earlier onset and more severe HCM and other sarcomeric genes (TNNT2, TNNI3, TPM1) are documented — double-variant carriers have substantially earlier-onset, more penetrant disease.

First-degree relatives of confirmed W792R carriers have a 50% probability of inheriting this allele. Cascade genetic testing enables early surveillance and lifestyle modification before structural remodeling has begun — the window of maximum preventive opportunity.