rs187830361 — MYBPC3 Trp792Arg (W792R)

Ultra-rare pathogenic missense variant in the C6 fibronectin domain of cardiac myosin-binding protein C that destabilizes domain folding and causes functional haploinsufficiency, leading to hypertrophic cardiomyopathy with early onset and high penetrance.

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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.

Genotype Interpretations

What each possible genotype means for this variant.

AA Non-carrier Normal

No MYBPC3 Trp792Arg variant; standard cardiac myosin-binding protein C function at this locus

You carry two copies of the reference A allele at rs187830361. Your cardiac myosin-binding protein C (cMyBP-C) has a normal tryptophan residue at position 792, maintaining the structural integrity of the C6 fibronectin type III domain. The pathogenic G allele (p.Trp792Arg) is not present in your genome at this locus. This is the genotype carried by essentially all individuals in population databases — the G allele is absent or near-absent across all ancestry groups in gnomAD, reflecting its extreme rarity and the strong association with autosomal dominant HCM.

AG Pathogenic Carrier High Risk

Heterozygous for MYBPC3 Trp792Arg — pathogenic variant for hypertrophic cardiomyopathy

The p.Trp792Arg substitution replaces a conserved hydrophobic core residue in the C6 domain of cMyBP-C with a positively charged arginine, destabilizing the fibronectin type III fold (computational ΔΔG −1.28 kcal/mol). Despite normal mRNA levels, the mutant protein is expressed at substantially reduced amounts — it is recognized as misfolded and degraded by the ubiquitin-proteasome pathway. The result is a cardiomyocyte that has only ~50% of functional cMyBP-C, which cannot adequately regulate myosin head super-relaxation. This drives hypercontractility, pathological hypertrophy, myocardial disarray, interstitial fibrosis, and eventually the structural phenotype of HCM: asymmetric left ventricular hypertrophy, dynamic outflow tract obstruction, and diastolic dysfunction.

Mouse knock-in data confirm that the mutation preferentially drives Ca2+-sensitizing actin interactions rather than inhibitory myosin interactions — a mechanism that increases myosin activation and sarcomere force output inappropriately at rest and during low-stress states. Over time, this energetically costly hypercontractility remodels the heart: cardiomyocytes hypertrophy, die, and are replaced by fibrotic scar tissue. Fibrosis creates the substrate for re-entrant arrhythmias and sudden cardiac death.

Because MYBPC3 HCM shows incomplete penetrance that is age-dependent, a currently normal echocardiogram does not mean this variant will remain clinically silent. Many carriers develop LVH only in their 4th or 5th decade. Surveillance must continue lifelong, with increased frequency during adolescence (rapid growth phase) and any period of cardiovascular stress.

Mavacamten (a selective cardiac myosin ATPase inhibitor) is now guideline-supported for symptomatic obstructive HCM and works precisely on the hypercontractility mechanism driven by variants like W792R — it is worth discussing with a specialist whether pre-symptomatic or early-symptomatic use is appropriate once LVH develops.

GG Homozygous Homozygous

Homozygous for MYBPC3 Trp792Arg — both alleles of cardiac myosin-binding protein C are affected; severe HCM phenotype expected

You carry two copies of the pathogenic G allele (p.Trp792Arg). This genotype has not been described in published human case reports — all known W792R carriers are heterozygous. Mouse knock-in data show that homozygous W792R mice develop severe hypertrophy, myofibrillar disarray, and fibrosis by postnatal day 10 and die by day 21, indicating the homozygous state is incompatible with normal cardiac development. If this result is confirmed, it would represent a profoundly serious cardiac finding requiring immediate expert evaluation. Technical confirmation from a fresh sample is essential before drawing clinical conclusions, as this genotype has not been observed in human populations and laboratory error must be excluded.