rs267606908 — MYH7 D906G

Pathogenic beta-myosin heavy chain missense variant causing a hypercontractile sarcomere; heterozygous carriers (CT) have high penetrance for hypertrophic cardiomyopathy and are at significant risk for sudden cardiac death and heart failure

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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. 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.

In muscle fiber studies, actin filaments translocated 34% faster over Asp906Gly myosin compared to wild-type.

The Evidence

rs267606908 was reviewed and classified as pathogenic by the ClinGen Cardiomyopathy Variant Curation Expert Panel33 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 US biochemical study estimated penetrance at 25%44 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."

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)55 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.

Genotype Interpretations

What each possible genotype means for this variant.

TT Non-carrier Normal

No MYH7 D906G mutation — standard baseline cardiac risk from this variant

You carry two copies of the common T allele at rs267606908, meaning your beta-myosin heavy chain protein is not affected by the Asp906Gly substitution. This is the expected genotype in essentially the entire general population; the C allele occurs in roughly 2 per 100,000 people globally. You do not carry this particular MYH7 pathogenic variant.

CT D906G Carrier High Risk

One copy of MYH7 D906G — significantly elevated hypertrophic cardiomyopathy risk

Clinical manifestations can include: - Asymmetric left ventricular hypertrophy, often maximal at the interventricular septum - Left ventricular outflow tract obstruction (LVOTO), causing exertional symptoms - Diastolic dysfunction, which may precede structural hypertrophy - Atrial fibrillation, a common complication of long-standing HCM - Sudden cardiac death, particularly in young people and competitive athletes - Progressive heart failure, including evolution to a dilated, reduced-ejection-fraction phenotype in a subset of carriers

Penetrance is incomplete and variable; some carriers live to old age with minimal manifestations while others develop severe disease in childhood or young adulthood. Age at assessment significantly affects apparent penetrance — surveillance over decades is required to exclude disease in genotype-positive, phenotype-negative individuals.

CC Homozygous D906G High Risk

Two copies of MYH7 D906G — extremely rare homozygous state; expected severe or lethal cardiac phenotype

No published clinical cases of homozygous MYH7 D906G have been documented in the literature, reflecting the extreme rarity of inheriting two copies of a rare pathogenic allele at this locus. Analogous homozygous states at other MYH7 pathogenic loci have been associated with lethal fetal or neonatal cardiomyopathy in the rare instances reported.

Before accepting a homozygous result clinically, independent confirmation by orthogonal sequencing (Sanger sequencing or a second platform) is warranted to exclude sequencing or genotyping artifact. If confirmed, immediate comprehensive cardiac evaluation and urgent cardiac genetics referral are required.