rs397516127 — MYH7 Arg663Cys (R663C)

Pathogenic missense variant in the beta-myosin heavy chain motor domain causing hypertrophic cardiomyopathy through a dominant-negative mechanism; documented in more than 15 unrelated HCM-affected individuals and absent from population databases

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MYH7 Arg663Cys — A Charge-Altering Mutation at the Heart's Molecular Engine

Every heartbeat begins at the sarcomere — the basic contractile unit of cardiac muscle, where the protein beta-myosin heavy chain11 beta-myosin heavy chain
the primary motor protein of the heart, encoded by MYH7, that generates the forceful contraction driving blood into the aorta with each beat physically pulls actin filaments to shorten the cell. The Arg663Cys variant introduces a single amino acid change in the myosin motor domain — the globular head where the force-generating power stroke occurs — substituting the positively charged arginine at position 663 with a neutral cysteine that is also capable of forming disulfide bonds. ClinVar classifies this as Pathogenic/Likely Pathogenic22 Pathogenic/Likely Pathogenic
VCV000042874, criteria provided, 16 of 22 submitting laboratories concur, no conflicts, and it is essentially absent from gnomAD's population database of over 700,000 sequenced individuals, consistent with a rare, high-penetrance disease allele.

The Mechanism

Codon 663 is situated in the myosin S1 (motor) domain33 myosin S1 (motor) domain
the ATPase-active globular head region that forms cross-bridges with actin and undergoes the conformational power stroke during muscle contraction. Arginine-663 is highly conserved across vertebrate species44 highly conserved across vertebrate species
evolutionary conservation of a residue indicates structural or functional importance; its replacement in any vertebrate species produces disease, underscoring its critical role in myosin function. The substitution of arginine (positively charged, guanidinium side chain) with cysteine (neutral, thiol side chain) is a charge-altering change — the same category of mutation that Watkins et al. (1992)55 Watkins et al. (1992) established as prognostically severe in familial HCM, associated with markedly reduced survival compared to charge-neutral variants.

The pathogenic mechanism is dominant-negative: the mutant MYH7 protein is synthesised from the one mutant allele and incorporated into sarcomeres alongside normal protein from the intact allele. Because sarcomeres assemble from mixtures of normal and mutant myosin, even one copy of the variant disrupts cross-bridge kinetics across the entire myofibril. Direct measurement in human HCM myocardium confirms that MYH7 mutations reduce maximum sarcomere force to 73 kN/m² versus 113 kN/m² in donor controls66 MYH7 mutations reduce maximum sarcomere force to 73 kN/m² versus 113 kN/m² in donor controls
a 35% reduction in force-generating capacity despite near-normal myofibril density, indicating intrinsic sarcomeric dysfunction rather than structural remodelling alone. Downstream, abnormal calcium handling compounds the defect: iPSC-derived cardiomyocytes from carriers of the closely related Arg663His variant77 Arg663His variant
a different amino acid substitution at the identical codon 663, also classified as pathogenic for HCM, rs371898076 showed elevated intracellular calcium, cellular enlargement, and contractile arrhythmia — phenotypes prevented by calcium channel inhibition. The combined effect of impaired force generation and disturbed calcium signalling drives progressive pathological hypertrophy, myocyte disarray, and interstitial fibrosis over years to decades.

The Evidence

The variant's pathogenicity rests on multiple independent lines of evidence evaluated by the ClinGen Inherited Cardiomyopathy Expert Panel88 ClinGen Inherited Cardiomyopathy Expert Panel, which adapted the ACMG/AMP classification framework specifically for MYH7. Key criteria include: PS4 (identified in more than 15 unrelated HCM-affected individuals), PM1 (location in the motor domain mutational hotspot), PM5 (other pathogenic changes at the same codon — Arg663His and Arg663Ser), and PM2 (absent from population databases). No population controls in gnomAD carry the A allele at the relevant frequency in any ancestry group (observed count: 3 out of 1,401,470 alleles, frequency 0.0000021).

Among all sarcomeric HCM mutations, MYH7 pathogenic variants are associated with particularly adverse outcomes99 MYH7 pathogenic variants are associated with particularly adverse outcomes. In a Chinese cohort of 52 MYH7 mutation carriers compared to 18 MYBPC3 carriers, MYH7 patients had seven sudden cardiac deaths versus zero in the MYBPC3 group, and mean survival was 45 years versus 73 years — a 28-year reduction. Van Driest et al. (2004)1010 Van Driest et al. (2004) found MYH7 mutation carriers present with HCM nearly a decade earlier than sarcomere-negative patients (mean 33 vs 43 years), have substantially greater left ventricular wall thickness, and undergo myectomy at twice the rate.

The 1992 founding observation by Watkins et al.1111 Watkins et al. remains instructive: charge-altering arginine substitutions in MYH7 — the precise category that includes Arg663Cys — were associated with mean age at death of 33 years, versus near-normal survival for charge-neutral substitutions. Arg663Cys replaces a charged arginine with a neutral cysteine, placing it squarely in this high-risk mutation class.

Practical Actions

For a carrier of the Arg663Cys variant, the clinical priority is structured cardiac surveillance starting at the time of genetic diagnosis, before symptoms appear. Transthoracic echocardiography establishes whether hypertrophy is already present and quantifies the resting and provoked left ventricular outflow tract (LVOT) gradient — the key determinant of obstructive physiology requiring intervention. Cardiac MRI adds late gadolinium enhancement (LGE) mapping of myocardial fibrosis, which independently predicts sudden death risk beyond conventional HCM risk factors.

Sudden cardiac death (SCD) risk stratification is the most consequential early decision. Current ESC guidelines apply the HCM Risk-SCD calculator to estimate 5-year SCD probability; an ICD (implantable cardioverter-defibrillator) is recommended for estimated risk ≥6%, and is considered for risk 4–6%. Carrying a pathogenic MYH7 variant — particularly one in the charge-altering category — is itself a clinical marker of higher severity that cardiologists incorporate into the risk assessment.

Obstructive HCM (gradient ≥30 mmHg) responds to medical therapy with beta-blockers or disopyramide. Refractory obstruction may require septal reduction (surgical myectomy or alcohol septal ablation). Mavacamten — a first-in-class cardiac myosin inhibitor approved by the FDA for obstructive HCM — directly addresses the hypercontractile mechanism of sarcomere mutations and is an important option for carriers who develop symptomatic obstruction.

Strenuous competitive sport is contraindicated until formal HCM evaluation is complete, given the risk of arrhythmia-triggered SCD during extreme exertion.

Interactions

Codon 663 is a mutational hotspot1212 mutational hotspot
three independent pathogenic substitutions at the same codon — Arg663His (rs371898076), Arg663Cys (this variant), and Arg663Ser — have all been classified as pathogenic or likely pathogenic for HCM in separate individuals and families. A carrier of Arg663Cys could theoretically also carry a second sarcomeric HCM mutation in MYBPC3, TNNT2, TNNI3, or another MYH7 variant; double sarcomeric mutation carriers have been shown in clinical cohorts to face markedly elevated risk of end-stage heart failure and malignant arrhythmias compared to single-variant carriers. Comprehensive sarcomere gene panel testing at the time of diagnosis will detect compound genotypes that substantially alter prognosis and management. If a second sarcomeric variant is found, the management threshold for ICD implantation and specialist referral should be reviewed with a cardiology team experienced in high-risk HCM.

Genotype Interpretations

What each possible genotype means for this variant.

GG Non-carrier Normal

No MYH7 Arg663Cys variant detected

You carry two copies of the reference G allele at this position. The MYH7 p.Arg663Cys pathogenic variant is not present in your genome at this locus. This ultra-rare variant is found in fewer than 2–3 individuals per million in population databases and is present only in individuals with hypertrophic cardiomyopathy or a family history of the condition. The common result — by an overwhelming margin — is two reference copies. This result does not exclude other genetic causes of HCM; over 1,500 pathogenic variants exist across more than 11 sarcomeric genes.

AG Carrier High Risk

Carries one copy of the MYH7 Arg663Cys pathogenic variant — hypertrophic cardiomyopathy risk

The Arg663Cys substitution sits in the myosin S1 motor domain — the ATPase-active region where cross-bridge formation and the force-generating power stroke occur. Arginine-663 is highly conserved across vertebrate evolution, indicating a structurally or functionally critical role. Replacing it with cysteine eliminates the positive charge of the arginine guanidinium group and introduces a thiol group capable of aberrant disulfide bond formation.

The mutant MYH7 protein is incorporated into sarcomeres alongside normal protein from the intact allele, and it disrupts cross-bridge kinetics across the entire myofibril even when only 50% of the myosin molecules are mutant. Direct force measurements in human HCM myocardium with MYH7 mutations show maximum sarcomere force of 73 kN/m² versus 113 kN/m² in donor controls — a 35% reduction. Abnormal calcium handling further compounds the sarcomeric defect, driving the pathological hypertrophy and interstitial fibrosis that characterise established HCM.

Among MYH7 pathogenic variants, charge-altering substitutions (arginine to a neutral or oppositely charged residue) are consistently associated with the most severe clinical outcomes. In Chinese cohort data (Wang 2008), MYH7 carriers had a mean survival of 45 years and seven sudden cardiac deaths among 52 carriers; MYBPC3 carriers averaged 73 years with zero sudden deaths. The 1992 Watkins study established that arginine-to-cysteine substitutions in MYH7 correlated with mean age at death of 33 years in affected families.

The variant's pathogenicity is further supported by PM1: codon 663 is a recognised mutational hotspot in the MYH7 motor domain, with two additional pathogenic variants at the same position — Arg663His and Arg663Ser — classified as pathogenic in ClinVar. Any consumer or research-grade genotyping result for this variant should be confirmed by a CLIA-certified clinical laboratory before medical decisions are finalised. Clinical-grade MYH7 sequencing panels also detect the full spectrum of pathogenic variants across the gene, which is important for cascade family planning.

AA Homozygous (Extremely Rare) High Risk

Appears to carry two copies of the MYH7 Arg663Cys pathogenic variant — an exceptionally rare finding requiring immediate verification

Homozygous pathogenic MYH7 mutations are not documented in surviving adults with standard-onset HCM. Dominant sarcomere gene mutations act through haploinsufficiency or dominant-negative mechanisms that are already fully manifest with one mutant copy. A homozygous state — both alleles producing Arg663Cys protein — would eliminate all wild-type myosin from the sarcomere, a configuration expected to produce lethal or severely debilitating cardiac disease from very early life.

Consumer and research-grade genotyping arrays can produce false-positive homozygous calls at ultra-rare loci where the chip was not designed to discriminate heterozygous from homozygous rare alleles. The prior probability of true homozygosity at this locus is essentially zero; the prior probability of a technical error at an ultra-rare site is substantially higher. Do not act on this result without laboratory confirmation.