rs371898076 — MYH7 Arg663His (R663H)

MYH7 Arg663His — The Sarcomere Mutation That Triggers Hypertrophic Cardiomyopathy and Atrial Fibrillation

Beta-myosin heavy chain (MYH7) is the molecular engine of the heart. Together with actin filaments, it generates the forceful contraction that drives blood out of the left ventricle with every beat. The Arg663His variant — a substitution of arginine for histidine at position 663 of the protein — sits directly in the myosin motor domain¹¹ myosin motor domain
The ATPase-powered globular head region where myosin physically binds actin and cycles through the power stroke, the precise region where force is generated. ClinVar classifies this variant as pathogenic, reviewed by an expert panel, and it has been documented in more than 30 unrelated individuals with confirmed hypertrophic cardiomyopathy (HCM).

The Mechanism

At codon 663, arginine — a large, positively charged amino acid — normally interacts with the actin filament at the myosin-actin interface during the cross-bridge cycle. Replacing it with histidine alters the local charge environment and changes how tightly myosin binds actin. The consequence, demonstrated in patient-specific iPSC-derived cardiomyocytes²² patient-specific iPSC-derived cardiomyocytes
A ten-member family cohort carrying Arg663His; iPSC-CMs fully recapitulated HCM pathology in vitro, Lan et al. Cell Stem Cell 2013, is dysregulated calcium cycling: resting intracellular Ca²⁺ is elevated, Ca²⁺ transients are abnormal, and cardiomyocytes develop contractile arrhythmias at the single-cell level. Crucially, pharmacological restoration of Ca²⁺ homeostasis prevented development of cellular hypertrophy and electrical irregularities in these models — identifying calcium dysregulation as a causal, not merely correlating, mechanism.

The structural consequence at the organ level is asymmetric left ventricular hypertrophy³³ asymmetric left ventricular hypertrophy
Predominantly in the proximal interventricular septum, though distribution varies across carriers in the same family. Unlike MYBPC3-related HCM, which tends to manifest later in life, MYH7 variants cause measurable LVH at younger ages, and the wall thickening seen with Arg663His was documented to increase approximately 40% over a 7-year follow-up — a slow but progressive course.

The Evidence

The foundational clinical study was published by Gruver, Fatkin, Seidman, and colleagues in 1999⁴⁴ Gruver, Fatkin, Seidman, and colleagues in 1999
24-individual kindred; 47% AF prevalence among adults with ventricular hypertrophy; p<0.001 vs. ungenotyped HCM populations. This family cohort established two distinctive features of Arg663His HCM: near-normal overall survival, and an extraordinarily high atrial fibrillation (AF) rate. Nearly half of adult carriers with ventricular hypertrophy developed AF — a rate far exceeding what is seen in typical HCM.

This AF predisposition was independently confirmed in a multinational HCM registry of 1,040 genotype-positive patients⁵⁵ multinational HCM registry of 1,040 genotype-positive patients
Mean follow-up 7.2 years; adjusted for age, sex, proband status, LA size, wall thickness, and peak gradient; Lee et al. Circ Heart Failure 2018. Among all MYH7 pathogenic variant carriers, the hazard ratio for new-onset AF was 1.7 (95% CI 1.1–2.6) compared to MYBPC3 carriers — the highest of any genotype group — after adjusting for established clinical AF risk factors. MYH7 variant carriers also showed earlier disease onset, greater left atrial dilation, and more extensive myocardial fibrosis, all of which structurally predispose to arrhythmia initiation.

Codon 663 is considered a mutational hotspot⁶⁶ mutational hotspot
A different variant at the same codon, Arg663Cys (rs193922376), is independently pathogenic; 15% of MYH7-positive HCM patients in one cohort had a variant at this codon, ClinVar VCV000042874 in MYH7. Haplotype analysis has shown that Arg663His is not a founder mutation — it has arisen independently multiple times in ethnically diverse populations, which further supports the functional importance of arginine at position 663.

Practical Implications

For a pathogenic MYH7 variant carrier, three clinical priorities stand out. First, cardiac imaging: the absence of detectable LVH at one point in time does not rule out future development — MYH7 penetrance is age-dependent, and repeat echocardiography every 1-2 years⁷⁷ repeat echocardiography every 1-2 years
ACC/AHA 2020 HCM guidelines recommend periodic clinical evaluation including ECG and echocardiogram for known sarcomere variant carriers is standard practice. Second, AF vigilance: the Arg663His variant in particular carries an exceptionally high AF rate, and palpitations, breathlessness, or fatigue in a carrier should prompt cardiac rhythm evaluation. Third, family cascade screening: because inheritance is autosomal dominant, each first-degree relative has a 50% chance of carrying the same variant and warrants genetic testing followed by cardiologic evaluation if positive.

Interactions

The most clinically relevant gene-gene interaction involves co-occurrence of pathogenic variants in both MYH7 and MYBPC3 — a "double heterozygous" state reported in a small proportion of HCM families. Double heterozygotes (carrying pathogenic variants in both genes simultaneously) tend to present with more severe hypertrophy, earlier age of onset, and a higher rate of adverse events including sudden cardiac death compared to single-gene carriers. If a carrier of this MYH7 variant also carries a pathogenic MYBPC3 variant (e.g., rs193922376 or other confirmed pathogenic alleles), their risk profile should be escalated accordingly and discussed with a specialized HCM center.