rs267606908 — MYH7 D906G

MYH7 D906G — A Hypercontractile Sarcomere Mutation with High Cardiac Risk

The heart's pumping power depends on the precise choreography of sarcomeric proteins — molecular motors that convert ATP into coordinated contraction. Beta-myosin heavy chain¹¹ Beta-myosin heavy chain
Encoded by MYH7; the dominant myosin isoform in adult ventricular cardiomyocytes, making up roughly 30% of total ventricular protein mass is the central force-generator of this system. rs267606908 replaces an aspartate at position 906 of this protein with a glycine — a conservative-looking swap that nonetheless disrupts the motor's kinetics profoundly. Carriers of the C allele face a substantially elevated risk of hypertrophic cardiomyopathy (HCM)²² hypertrophic cardiomyopathy (HCM)
A structural heart disease defined by unexplained left ventricular hypertrophy not caused by pressure overload; the most common inherited cardiac condition, affecting 1 in 500 people overall, and are at risk for sudden cardiac death and progressive heart failure.

The Mechanism

Beta-myosin works through a mechanochemical cycle: ATP binds to the motor domain, hydrolysis cocks the lever arm, actin binding triggers force release (the power stroke), and ADP dissociation resets the cycle. The Asp906 residue sits in a region critical for Switch-2 closure³³ Switch-2 closure
A structural movement within the myosin motor domain that gates the release of the hydrolysis products; defective Switch-2 closure slows the ATPase cycle and traps the motor in a force-producing state. Replacing Asp906 with glycine disrupts this geometry in two measurable ways: the motor's maximum ATPase rate drops ~30%, and the hydrolysis step itself is slowed 3-fold compared to wild-type.

Yet paradoxically, force production increases. Single-molecule laser trap experiments⁴⁴ Single-molecule laser trap experiments
Sommese et al. used optical tweezers to measure the force a single myosin molecule produces during its power stroke; the technique isolates individual motor events from the ensemble showed D906G myosin generates approximately 50% more force per power stroke (2.1 vs 1.4 piconewtons) than wild-type, and ensemble loaded-motility assays confirmed this hypercontractile phenotype. In muscle fiber studies, actin filaments translocated 34% faster over Asp906Gly myosin compared to wild-type. The result is a motor that generates excessive force while cycling inefficiently — a combination that imposes chronic mechanical stress on cardiomyocytes, activates pro-fibrotic signaling cascades, and drives pathological hypertrophy.

A 2024 transgenic pig model reproduced the human phenotype with high fidelity. Animals carrying the D906G mutation⁵⁵ D906G mutation
Modeled in the closely related MYH7 isoform of the pig heart developed ventricular fibrosis, cardiomyocyte loss, and activated TGF-β/Smad2/3, ERK1/2, and Nox4/ROS/NF-κB signaling — all pathways implicated in HCM progression and end-stage cardiac remodeling.

The Evidence

rs267606908 was reviewed and classified as pathogenic by the ClinGen Cardiomyopathy Variant Curation Expert Panel⁶⁶ ClinGen Cardiomyopathy Variant Curation Expert Panel
An NIH-funded consortium of cardiomyopathy genetics experts that systematically reviews variant evidence using standardized ACMG/AMP criteria in December 2016. With 18 independent ClinVar submissions all converging on "pathogenic" status, this is among the better-curated HCM variants in the genome.

Clinical penetrance data are sobering. A Chinese family study⁷⁷ Chinese family study
Wang et al. 2024, published in the Chinese Heart Journal, studying 5 unrelated probands and their families found 12 of 13 mutation carriers diagnosed with HCM, with 2 sudden cardiac deaths, 2 SCD-survival events, and 3 deaths before age 30 among the families. A earlier US biochemical study estimated penetrance at 25%⁸⁸ estimated penetrance at 25%
Alpert et al. 2005; penetrance varied from 25% for Asp906Gly to 46% for Leu908Val among family members examined, noting that "despite the low penetrance, hypertrophy was severe in several heterozygotes." This variability — 25-90% depending on the study population — reflects the influence of genetic modifiers, age at assessment, and environmental triggers on phenotypic expression.

At the severe end of the spectrum, a Japanese case series⁹⁹ Japanese case series
Naito et al. 2023, three patients with MYH7 R453 variants — the residue at protein position 453 in the older, alternative numbering that corresponds to Asp906 in current HGVS notation documented rapid progression from preserved ejection fraction to end-stage heart failure, requiring cardiac resynchronization defibrillators, left ventricular assist devices, and transplant listing. Histopathology showed cardiomyocyte disarray and interstitial fibrosis — the classic end-organ signature of HCM progression.

Practical Implications

The central action for any carrier of the C allele is cardiac surveillance: periodic echocardiograms and ECGs, ideally under the care of a cardiomyopathy specialist. The goal is early detection of hypertrophy, outflow tract obstruction, and arrhythmia — all three of which are more manageable when caught before symptoms develop. Competitive sport carries elevated sudden death risk for HCM carriers and requires a specialist evaluation before participation.

Pharmacological options for symptomatic HCM now include myosin inhibitors (mavacamten, aficamten) — drugs designed precisely to counteract the hypercontractile state that MYH7 pathogenic variants produce. These are prescription medications requiring specialist management but represent a mechanism-matched intervention for this class of variant. Beta-blockers and calcium channel blockers remain first-line agents for symptom control and rate management in HCM with obstruction.

Cascade genetic testing in first-degree family members is standard of care. Each child, sibling, or parent of a confirmed carrier has a 50% chance of carrying the same variant; early identification in asymptomatic relatives allows prophylactic monitoring before structural disease develops.

Interactions

HCM phenotype severity from MYH7 pathogenic variants is modified by sarcomeric modifier variants elsewhere in the genome — particularly in genes encoding titin (TTN)¹⁰¹⁰ titin (TTN)
The largest human protein, functioning as the sarcomere's molecular spring and ruler; rare TTN variants can act as independent HCM or DCM causes, alpha-tropomyosin (TPM1, rs117022535), and myosin-binding protein C (MYBPC3). Compound heterozygosity — carrying pathogenic variants in two sarcomeric genes simultaneously — is associated with earlier onset and more severe disease than single-gene HCM. The related variant rs121913625 (MYH7 R453C, Arg453Cys) is a distinct pathogenic HCM mutation at a different residue in the same gene with overlapping but not identical biochemical consequences.