rs199474703 — MYL3 Arg94His (R94H)

Rare pathogenic missense variant in the myosin essential light chain causing hypertrophic cardiomyopathy with high penetrance in affected families

See your personal result for MYL3

Upload your DNA data to find out which genotype you carry and what it means for you.

Upload your DNA data

Works with 23andMe, AncestryDNA, and other DNA test exports. Results in under 60 seconds.

MYL3 Arg94His — A High-Penetrance Sarcomeric Variant for Hypertrophic Cardiomyopathy

Your heart's pumping power comes from millions of sarcomeres11 sarcomeres
The sarcomere is the basic contractile unit of cardiac muscle. Each sarcomere contains an interdigitating lattice of thick (myosin) and thin (actin) filaments that slide past each other to produce contraction working in concert. The MYL3 gene encodes the essential myosin light chain (ELC), a structural component of the myosin thick filament that stabilizes the lever arm region and regulates the force and speed of cardiac muscle contraction. The Arg94His substitution — a single amino acid change replacing arginine with histidine at position 94 of the ELC — disrupts this regulation in a way that causes the heart muscle to thicken abnormally, a condition called hypertrophic cardiomyopathy (HCM).

HCM is the most common inherited cardiac disease, affecting approximately 1 in 500 people overall. However, MYL3 mutations are a rare cause of HCM — responsible for less than 1% of all sarcomeric HCM cases. The Arg94His variant in particular has been documented in a small number of families worldwide and is classified as pathogenic by eight independent clinical laboratories22 pathogenic by eight independent clinical laboratories
ClinVar VCV000031777: submissions from LabCorp Genetics, Women's Health and Genetics/LabCorp, Ambry Genetics, GeneDx, Mass General Brigham, NIH All of Us, Color Diagnostics, and CHEO Genetics.

The Mechanism

The MYL3 ELC wraps around the myosin heavy chain lever arm33 lever arm
The lever arm is the portion of myosin that amplifies the small conformational change at the catalytic domain into a large stroke movement that pulls actin filaments. Light chains stabilize this lever arm against mechanical stress. Arginine-94 sits in a functionally critical region of the ELC. Replacing the positively charged arginine with histidine (which carries a smaller, uncharged side chain at physiological pH) is predicted to disrupt local protein folding and the ELC's interaction with the myosin heavy chain, altering the super relaxed state of myosin — a low-energy resting state that is disrupted in HCM-associated ELC mutations. The net result is hypercontractility of the sarcomere, leading over time to pathological left ventricular hypertrophy, diastolic dysfunction, and in some cases left ventricular outflow tract obstruction.

The Evidence

The primary evidence for MYL3 Arg94His comes from a Japanese family study44 Japanese family study
Nomura et al., J Cardiol, 2016 (N=7 family members, 5 affected; followed by registry screening of 600 HCM patients) that used whole-exome sequencing combined with bioinformatic filtering to identify the variant. Among carriers in that family, disease penetrance was 88% — very high for an HCM gene. All clinically affected carriers showed asymmetric septal hypertrophy with a maximum left ventricular wall thickness of 18±3mm without outflow obstruction. Two additional carriers were found in a registry of 600 HCM patients, supporting that this is a genuine pathogenic variant rather than a private family mutation.

By contrast, other MYL3 variants (such as the p.Val79Ile variant55 p.Val79Ile variant
Andersen et al., Biochem Res Int, 2012 — nine heterozygous carriers in a Danish family) show much lower penetrance (~40%) and late onset. This variability is consistent with the broader GeneReviews HCM data66 GeneReviews HCM data
Cirino et al., updated 2025 — MYL3 overall penetrance ~32%, the lowest among sarcomeric HCM genes when all variants are pooled. The Arg94His variant appears to be at the higher end of MYL3 penetrance, based on the Nomura family data, though the evidence is limited to a small number of families. Eight independent clinical laboratories have independently classified it as pathogenic or likely pathogenic, providing strong multi-submitter validation.

In terms of population frequency, Arg94His is extremely rare: gnomAD v4 exomes identified only 7 T alleles among over 730,000 alleles examined globally, exclusively in European and Latino ancestry groups.

Practical Actions

For carriers of MYL3 Arg94His, the central priorities are: (1) confirm the diagnosis with a specialist, (2) establish regular cardiac surveillance, and (3) arrange cascade testing for first-degree relatives.

Unlike many common HCM genes (MYBPC3, MYH7) where genotype-specific prognosis is well-characterized, MYL3 Arg94His has been observed in relatively few families. Standard HCM management — echocardiography every 1–2 years, ambulatory ECG monitoring, exercise testing, and SCD risk stratification — applies. Drug therapy (beta-blockers, calcium channel blockers) addresses symptoms; septal reduction therapy (myectomy or alcohol ablation) is reserved for refractory obstructive cases. The newer selective cardiac myosin inhibitor mavacamten is approved for obstructive HCM and may be relevant if outflow obstruction develops.

Interactions

MYL3 variants have been observed to interact with other sarcomeric HCM genes. Individuals carrying two sarcomeric pathogenic variants (compound or digenic) show substantially worse outcomes — a hazard ratio of 7.5 for adverse events such as cardiac transplantation or ICD placement77 hazard ratio of 7.5 for adverse events such as cardiac transplantation or ICD placement
Cirino et al., GeneReviews, 2025 — based on registry data across sarcomeric HCM genes compared to single-variant carriers. This means that if a carrier of MYL3 Arg94His also carries a pathogenic variant in MYBPC3, MYH7, TNNT2, or another sarcomeric gene, clinical severity is likely to be substantially greater.

MYL3 is an essential light chain (encoded by chromosome 3), distinct from the regulatory light chain encoded by MYL2. Variants in ACTC1 (cardiac actin, rs193922680) affect the thin filament partner of myosin and can produce overlapping HCM phenotypes through a different molecular mechanism.

Genotype Interpretations

What each possible genotype means for this variant.

CC No MYL3 Arg94His Normal

No MYL3 Arg94His variant — not at elevated HCM risk from this variant

You carry two copies of the reference MYL3 allele at this position. You do not have the Arg94His variant and are not at elevated risk for hypertrophic cardiomyopathy from this specific mutation. More than 99.999% of the general population shares this result. HCM can still arise from many other sarcomeric gene variants, but this particular mutation is not contributing to your risk.

CT MYL3 Arg94His Carrier High Risk

Carries MYL3 Arg94His — pathogenic variant for hypertrophic cardiomyopathy

MYL3 encodes the essential myosin light chain, a structural component of the sarcomeric thick filament. The Arg94His substitution is predicted to disrupt the ELC's interaction with the myosin heavy chain lever arm, promoting a hypercontractile sarcomere state characteristic of HCM.

The primary evidence comes from a Japanese family study (Nomura et al., 2016, PMID 26443374) identifying MYL3 c.281G>A (p.Arg94His) in seven family members (five clinically affected). Penetrance was 88%. All affected carriers had asymmetric septal hypertrophy with maximum LVWT of 18±3mm and no outflow obstruction. Two additional carriers were found by screening 600 HCM registry patients. The variant is classified as pathogenic/likely pathogenic by eight clinical laboratories (ClinVar VCV000031777, multiple submitters, no conflicts).

Overall MYL3 penetrance across all variants is ~32% per GeneReviews — the lowest among sarcomeric HCM genes. However, the Arg94His variant specifically showed 88% penetrance in the Nomura family, suggesting it is a high-penetrance allele within MYL3. Given the limited published family data, some uncertainty remains around penetrance estimates for this specific variant.

Clinical management follows standard HCM guidelines. Echocardiography and ambulatory ECG monitoring every 1–2 years are the cornerstone of surveillance. SCD risk is assessed using validated tools incorporating: maximum LVWT, family history of SCD, non-sustained VT on Holter, unexplained syncope, LV apical aneurysm, and LVEF. Mavacamten (a selective cardiac myosin inhibitor) is approved for symptomatic obstructive HCM.

Autosomal dominant inheritance means each biological child of a carrier has a 50% chance of inheriting the variant.

TT Homozygous MYL3 Arg94His Homozygous

Homozygous for MYL3 Arg94His — extremely rare; clinical significance uncertain

MYL3 Arg94His homozygosity has not been reported in any published series. In other sarcomeric HCM genes (MYH7, MYBPC3), homozygous pathogenic variants are rare and may be associated with more severe early-onset disease compared to heterozygosity, but exceptions exist. For MYL3, a parallel autosomal recessive mechanism has been documented for different variants (Osborn et al., 2021, PMID 33288880), where homozygous loss-of-function variants cause a distinct cardiomyopathy phenotype with variable severity and sudden cardiac death. Whether homozygous Arg94His produces a more severe dominant-mechanism phenotype or partially recapitulates the recessive loss-of-function phenotype is unknown.

Genetic result confirmation is essential before clinical decisions are made. Whole-exome or genome sequencing re-review, or direct Sanger sequencing, can confirm true homozygosity versus a heterozygous call with reduced coverage on one allele.