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

Rare pathogenic missense variant at the last nucleotide of MYBPC3 exon 23, causing aberrant splicing and haploinsufficiency; strongly associated with hypertrophic cardiomyopathy (autosomal dominant)

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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.

Genotype Interpretations

What each possible genotype means for this variant.

CC Non-carrier Normal

No MYBPC3 Asp770Asn variant detected — standard cardiac risk at this locus

You carry two copies of the reference C allele at this position. You do not carry the rare rs36211723 pathogenic variant. The vast majority of people (>99.98%) share this genotype. Your MYBPC3 gene is unaffected at this specific site, and you face no elevated risk of MYBPC3 Asp770Asn-related hypertrophic cardiomyopathy.

Note that HCM can be caused by variants in many other genes — this result addresses only this specific MYBPC3 variant and does not rule out other hereditary cardiomyopathy causes.

CT Pathogenic Carrier Carrier

Pathogenic MYBPC3 variant detected — hereditary HCM risk, cardiac evaluation warranted

The p.Asp770Asn substitution falls at the critical last nucleotide of MYBPC3 exon 23. At this position, the genomic C (GRCh38 plus-strand reference) is replaced by T in your genome — corresponding to the coding-strand change c.2308G>A. Multiple in silico splice predictors identified disruption of the exon 23 splice donor signal, and this was confirmed experimentally: RT-PCR of cardiac tissue from Asp770Asn carriers detected only wild-type MYBPC3 transcript, indicating the mutant mRNA is eliminated by nonsense-mediated decay before it can be translated.

The result is haploinsufficiency — your two copies of MYBPC3 produce roughly half the normal amount of functional cMyBP-C protein. Human myectomy data from confirmed MYBPC3 pathogenic variant carriers show approximately 24% lower total MyBP-C protein than donor controls (p<0.0005). This protein deficit alters thick-filament mechanics: myosin cross-bridges become dysregulated, shifting the sarcomere toward hypercontractility and impaired relaxation, which over time drives concentric ventricular hypertrophy and diastolic dysfunction.

This specific variant has been reported in association with both hypertrophic cardiomyopathy and left ventricular noncompaction, suggesting that the phenotypic spectrum of MYBPC3 haploinsufficiency is broader than classic HCM alone. The 2024 AHA/ACC HCM guidelines classify pathogenic sarcomere variant carriers as being at elevated risk for adverse outcomes including ventricular arrhythmias and sudden cardiac death, justifying lifelong structured surveillance.

Any consumer genotyping result for this variant — including this one — should be confirmed by a CLIA-certified clinical laboratory before medical decisions are made.

TT Homozygous (Extremely Rare) Homozygous

Both MYBPC3 alleles carry the pathogenic Asp770Asn variant — high probability of severe early-onset HCM

You appear to carry the pathogenic T allele on both copies of chromosome 11 at this position. This is an extraordinarily rare finding — the T allele frequency is approximately 1-2 per 100,000, making TT homozygosity a probability of less than 1 in 10 billion by chance. This result should be confirmed immediately by a CLIA-certified clinical-grade genetic test.

If confirmed, MYBPC3 compound homozygosity or true homozygosity for a pathogenic variant is associated with severe cardiomyopathy — in documented case reports, biallelic MYBPC3 pathogenic variants cause neonatal or early-childhood onset of severe, often life-threatening cardiomyopathy. This is categorically distinct from the adult-onset, variably penetrant HCM seen in heterozygous carriers.

This result requires immediate cardiology evaluation. Do not wait for a scheduled appointment — contact a cardiologist or emergency cardiac genetics service directly.