rs11570112 — MYBPC3 Gln998X

Pathogenic truncating variant in cardiac myosin-binding protein C causing haploinsufficiency; heterozygous carriers develop hypertrophic cardiomyopathy through sarcomere dysfunction from reduced functional cMyBP-C levels

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When the Sarcomere's Brake Loses Half Its Material

The heart's ability to contract and relax is governed by molecular machines called sarcomeres — the repeating structural units of cardiac muscle fibers. One of their key regulatory proteins is cardiac myosin-binding protein C (cMyBP-C)11 cardiac myosin-binding protein C (cMyBP-C)
Encoded by MYBPC3 on chromosome 11; a large (~150 kDa) modular protein that tethers the thick (myosin) filament and acts as a spring-loaded brake on myosin motor activity. The rs11570112 variant — a C-to-T change on the coding strand (plus-strand: G>A) at position 2,992 of the MYBPC3 transcript — creates a premature stop codon at amino acid 998 (p.Gln998Ter, also written Q998X or Gln998*). The resulting truncated mRNA is rapidly destroyed by nonsense-mediated decay (NMD)22 nonsense-mediated decay (NMD)
A cellular surveillance pathway that degrades transcripts containing premature stop codons to prevent production of potentially toxic truncated proteins, so essentially no truncated cMyBP-C protein is produced. The outcome is that one functional MYBPC3 allele must supply all of the protein — and in many carriers, this is not enough.

This variant is classified as Pathogenic in ClinVar33 Pathogenic in ClinVar
VCV000180993; criteria provided, multiple submitters, no conflicts; last evaluated October 2023 for hypertrophic cardiomyopathy (HCM). It is one of hundreds of individually rare truncating MYBPC3 variants; collectively, truncating MYBPC3 mutations account for approximately 50% of all identified HCM-causing mutations, making MYBPC3 the most commonly mutated gene in this condition.

The Mechanism

cMyBP-C functions as a molecular brake on myosin motor activity. It holds myosin heads in a super-relaxed state (SRX)44 super-relaxed state (SRX)
An energy-conserving "parked" configuration of myosin heads — the SRX minimizes ATP consumption between heartbeats and limits the fraction of motors available for active contraction during diastole, preventing excessive contractility. The Gln998X stop-gain creates a transcript that is degraded before translation, eliminating ~80% of the C-terminal domain. As Toepfer et al. demonstrated in Science Translational Medicine55 Toepfer et al. demonstrated in Science Translational Medicine
PMID 30674652; iPSC-derived cardiomyocytes and cardiac muscle fiber experiments from the Seidman laboratory at Harvard, stepwise reduction of cMyBP-C protein causes reciprocal augmentation of myosin contractility — the brake is weakened and more myosin motors are released from the SRX into the active pool.

Human cardiac tissue studies confirm the mechanism directly: Marston et al., Circulation Research, 200966 Marston et al., Circulation Research, 2009
n=37 surgical myectomy samples from HCM patients and donor controls measured MyBP-C protein levels in myofibrils from patients carrying MYBPC3 mutations and found a significant ~24% reduction versus controls (p<0.0005), with no detectable truncated peptides — confirming haploinsufficiency, not a poison-peptide mechanism. The consequence at the organ level is pathological hypertrophy: the overactive sarcomeres trigger compensatory thickening of the ventricular wall, which ultimately impairs relaxation, stiffens the chamber, and can progress to outflow tract obstruction or arrhythmia.

The Evidence

Penetrance for MYBPC3 pathogenic variants is substantial but incomplete and age-dependent. A key European cohort study (Michels et al., European Heart Journal, 200977 Michels et al., European Heart Journal, 2009
PMID 19666645; 76 mutation carriers from 32 families, mean age 42 years) found that 41% of MYBPC3 mutation carriers had diagnosable HCM on cardiac imaging. Importantly, MYBPC3 carriers develop overt disease at an older age than MYH7 carriers (p=0.01) — a well-replicated observation suggesting a more gradual haploinsufficiency mechanism compared to the dominant-negative effects of most MYH7 missense mutations. Male carriers manifested disease earlier and more frequently than female carriers (p=0.04).

Functional experiments with engineered heart tissue88 engineered heart tissue
PMID 27108529; Wijnker et al., 2016, using human iPSC-derived cardiomyocytes assembled into 3D cardiac constructs established a protein-level threshold: haploinsufficiency only impairs contractile function when cMyBP-C falls below approximately 73% of normal levels. Because truncating variants provide no functional protein from the mutant allele, the entire burden falls on the wild-type allele, and many carriers do fall below this threshold — particularly under cardiac stress. A mouse haploinsufficiency model (Barefield et al., JMCC, 201599 Barefield et al., JMCC, 2015
PMID 25463273) confirmed that heterozygous MYBPC3-truncation animals develop exacerbated hypertrophy and reduced ejection fraction when subjected to pressure overload, with myofilament cMyBP-C content dropping significantly below that of stressed wild-type animals.

The Gln998X nonsense-mediated mRNA degradation pathway is well established: Helms et al. 20141010 Helms et al. 2014
PMID 25031304; Circulation: Cardiovascular Genetics showed that truncating MYBPC3 mutations produce mutant:wild-type mRNA ratios of approximately 1:5, consistent with efficient NMD, versus 1:1 for missense mutations. Total MYBPC3 mRNA increases ~9-fold as a compensatory response, but full-length protein levels remain reduced and no truncated peptides accumulate.

Practical Implications

A positive result for this pathogenic variant requires proactive clinical management even in the absence of symptoms, because HCM can present first as sudden cardiac death — especially during intense physical exertion. The 2024 AHA/ACC HCM guidelines (Ommen et al., Circulation, 20241111 Ommen et al., Circulation, 2024
PMID 38718139) emphasize genetic cascade testing of first-degree relatives, regular echocardiographic surveillance of carriers, and individualized sudden cardiac death risk stratification. All carriers should be evaluated by a cardiologist with HCM expertise; echocardiography at the time of diagnosis and at regular intervals thereafter is the standard of care.

High-intensity competitive sport should be approached with extreme caution. For carriers who develop obstructive HCM, septal reduction therapy (surgical myectomy or alcohol septal ablation) can relieve outflow tract obstruction, and the novel cardiac myosin inhibitor mavacamten (targeting the same myosin overactivation pathway identified in laboratory studies) is now guideline-approved for symptomatic obstructive HCM.

Interactions

MYBPC3 Gln998X does not act in isolation. Modifier loci — particularly variants in renin-angiotensin-aldosterone pathway genes — influence the extent of fibrosis and hypertrophy in MYBPC3 variant carriers. Compound heterozygosity for two MYBPC3 variants (one in each allele) has been reported in Japanese HCM cohorts (PMID 22112859) and produces a more severe phenotype, effectively eliminating all functional cMyBP-C and mimicking the homozygous knockout phenotype seen in mice. Thin-filament HCM variants (TPM1 E180G, rs1048945021212 TPM1 E180G, rs104894502; TNNT2 variants, rs362117231313 TNNT2 variants, rs36211723) that independently increase Ca²⁺ sensitivity could compound with MYBPC3 haploinsufficiency through additive sarcomere overactivation, though the specific combination of Gln998X with thin-filament variants has not been studied in a published cohort.

Genotype Interpretations

What each possible genotype means for this variant.

GG Non-carrier Normal

Normal MYBPC3 sequence — no Gln998X variant detected

You carry two copies of the reference G allele at rs11570112, meaning you do not carry this MYBPC3 pathogenic truncating variant. The Gln998X stop-gain allele is absent from your genome at this position. Your cMyBP-C protein production from this locus is unaffected by this specific variant. About 99.85% of people share this genotype globally — the pathogenic A allele is extremely rare.

AG Pathogenic Carrier High Risk

Pathogenic MYBPC3 truncating variant detected — haploinsufficiency risk for HCM

The p.Gln998Ter stop codon truncates approximately 20% of the cMyBP-C C-terminus, eliminating critical domains that anchor the protein to the thick filament and regulate myosin ATPase activity. Because the mutant transcript is eliminated by nonsense-mediated decay (mutant:wild-type mRNA ratio ~1:5), no truncated protein accumulates — the sole consequence is quantitative reduction in functional cMyBP-C, falling below the ~73% threshold needed to maintain normal sarcomere mechanics.

At the cellular level, reduced cMyBP-C releases myosin motors from the super-relaxed state, increasing the number of force-generating cross-bridges during both systole and diastole. Over years to decades, this hypercontractile environment drives pathological hypertrophy, interstitial fibrosis, and microvascular dysfunction — the triad that underlies the clinical HCM phenotype.

Penetrance is age-dependent and sex-influenced: male carriers develop disease earlier and more frequently than female carriers. Not all carriers develop overt HCM — some remain phenotype-negative on echocardiography throughout life, but may still transmit the variant to children with full penetrance risk. Even phenotype-negative carriers face elevated arrhythmic risk, and sudden cardiac death as the first manifestation (without prior symptoms or echo findings) is well documented in MYBPC3 families.

First-degree relatives (parents, siblings, children) each have a 50% probability of inheriting this autosomal dominant pathogenic variant. Cascade genetic testing is guideline-recommended for all first-degree relatives of confirmed carriers.

AA Homozygous High Risk

Homozygous MYBPC3 Gln998X — severe biallelic cMyBP-C deficiency

In mice, complete elimination of MYBPC3 (homozygous knockout) leads to a dilated cardiomyopathy phenotype with massively reduced systolic function within weeks of birth — far more severe than the heterozygous HCM phenotype. If a homozygous human Gln998X carrier exists (compound heterozygosity would be far more likely clinically), both MYBPC3 alleles produce NMD-degraded transcripts, leaving zero functional cMyBP-C. The resulting sarcomere hypercontractility would be far beyond what causes HCM in heterozygotes; the phenotype may be a severe dilated or mixed cardiomyopathy rather than classic HCM.

Compound heterozygosity (two different MYBPC3 truncating variants, one on each chromosome) produces a comparable phenotype and has been reported in Japanese HCM cohorts. Pediatric presentations are typical in biallelic severe MYBPC3 disease.