rs36211723 — MYBPC3 Asp770Asn (c.2308G>A)

MYBPC3 Asp770Asn — A Splice-Disrupting Variant at the Heart of Hereditary Cardiomyopathy

The MYBPC3 gene encodes cardiac myosin-binding protein C (cMyBP-C)¹¹ cardiac myosin-binding protein C (cMyBP-C)
a thick-filament regulatory protein that modulates the interaction between myosin and actin during each heartbeat. Functioning like a molecular brake on sarcomeric contraction, cMyBP-C is also phosphorylated in response to beta-adrenergic stimulation, allowing the heart to increase its output during exertion. Pathogenic variants in MYBPC3 are the single most common identified cause of hypertrophic cardiomyopathy (HCM)²² hypertrophic cardiomyopathy (HCM)
abnormal thickening of the heart muscle, particularly the interventricular septum, causing impaired filling and obstruction of blood flow, accounting for 40–50% of all genetically solved HCM cases.

The rs36211723 variant substitutes cytosine for thymine at position 2308 of the coding sequence — on the plus (genomic) strand, C is replaced by T at chromosome 11:47338520. Because MYBPC3 is transcribed from the minus strand, this plus-strand C>T change corresponds to a coding-strand G>A transition at the last nucleotide of exon 23, written as c.2308G>A. The resulting amino acid change, p.Asp770Asn, is classified as pathogenic by 18 of 23 ClinVar submitters, with no conflicts.

The Mechanism

What makes rs36211723 unusual is that the pathogenic effect operates through splicing disruption rather than direct protein dysfunction³³ splicing disruption rather than direct protein dysfunction
the substitution falls at the final base of exon 23, a position critical for the exon-intron splice donor signal. Multiple in silico tools predicted elimination of the splice donor site, and experimental confirmation came from RNA analysis of cardiac tissue from patients carrying the variant. RT-PCR of MYBPC3 transcripts from Asp770Asn carriers⁴⁴ RT-PCR of MYBPC3 transcripts from Asp770Asn carriers
reverse-transcriptase PCR amplifying across exons 22–24 detected only wild-type sequence — the mutant mRNA was completely absent, indicating that aberrant splicing leads to nonsense-mediated decay (NMD)⁵⁵ nonsense-mediated decay (NMD)
a cellular quality-control pathway that degrades mRNAs containing premature stop codons or aberrant splice products.

The consequence is haploinsufficiency⁶⁶ haploinsufficiency
the single functional copy of the gene produces insufficient protein to maintain normal sarcomere architecture. Human myectomy studies confirmed that MYBPC3 protein levels are measurably reduced in HCM patient cardiac tissue — approximately 24% below donor controls (p<0.0005) — with no detectable truncated peptides, ruling out a dominant-negative mechanism. Reduced cMyBP-C alters myosin cross-bridge kinetics, shifting the sarcomere toward a hypercontractile state that drives pathological concentric hypertrophy and diastolic dysfunction over time.

The Evidence

ClinVar documents 18 independent submitters classifying rs36211723 as pathogenic, with the variant reported in more than 15 unrelated individuals with HCM and segregating with disease in at least one family. The variant has also been associated with left ventricular noncompaction cardiomyopathy⁷⁷ left ventricular noncompaction cardiomyopathy
a congenital myocardial disorder where the inner layers of the heart fail to compact properly, suggesting MYBPC3 haploinsufficiency can manifest across a spectrum of structural phenotypes.

MYBPC3-related HCM is characterised by incomplete, age-dependent penetrance⁸⁸ incomplete, age-dependent penetrance
not all variant carriers develop detectable HCM in their lifetime, and those who do often present late. Echocardiographic penetrance in carriers under 50 years is approximately 40–65%; this rises to 70–100% in carriers over 55. Cardiac MRI improves detection to 87.2% even in echocardiographically negative carriers. Women with MYBPC3 mutations develop phenotypic HCM approximately 6–13 years later than men on average, though once affected they show worse prognosis.

Carriers of pathogenic MYBPC3 variants face a twofold greater risk of adverse cardiac outcomes and a fourfold higher risk of ventricular arrhythmias compared to HCM patients without identifiable sarcomere mutations, according to Sarcomeric Human Cardiomyopathy Registry data. Sudden cardiac death risk is elevated, particularly in individuals with high-risk features on imaging⁹⁹ high-risk features on imaging
maximal wall thickness ≥30 mm, left ventricular outflow tract obstruction, late gadolinium enhancement on MRI, or family history of SCD.

Practical Actions

Carriers identified genetically but without clinical HCM (genotype-positive, phenotype-negative) require structured cardiac surveillance. The 2024 AHA/ACC HCM guidelines recommend ECG and cardiac imaging every 3–5 years for adult G+/P− carriers. For adolescent carriers (ages 10–20), ESC guidelines recommend annual monitoring given the higher rate of phenotypic conversion in that window.

If HCM is confirmed, management is guided by symptom burden and obstruction severity. Mavacamten — the first FDA-approved cardiac myosin inhibitor — is now a guideline-directed option for symptomatic obstructive HCM, directly targeting the sarcomeric hypercontractility caused by cMyBP-C haploinsufficiency. Beta-blockers and non-dihydropyridine calcium-channel blockers remain first-line for symptom management.

First-degree relatives (parents, siblings, children) of rs36211723 carriers have a 50% probability of inheriting the variant. Cascade genetic testing followed by structured cardiac surveillance is recommended for all at-risk relatives. Clinical-grade confirmatory testing is essential before acting on any consumer or research genotyping result for this variant.

Interactions

MYBPC3 Asp770Asn operates through haploinsufficiency — a single pathogenic copy is sufficient for disease risk. Compound heterozygosity (two MYBPC3 pathogenic variants in trans) produces far more severe, often neonatal-onset cardiomyopathy. If a carrier has a child with another MYBPC3 carrier, that child has a 25% chance of inheriting two pathogenic copies, substantially increasing severity risk.

Variants in other sarcomere genes — particularly MYH7 (rs121913629, beta-myosin heavy chain), TNNT2 (cardiac troponin T), and TNNI3 (cardiac troponin I) — can compound MYBPC3-mediated HCM risk when co-inherited. However, quantified combined-genotype risk estimates for rs36211723 specifically with other sarcomere variants are not yet published.