MYL3 – Hypertrophic Cardiomyopathy

Hypertrophic cardiomyopathy (HCM) is most often inherited in an autosomal dominant fashion with incomplete penetrance. MYL3 encodes the myosin essential light chain, and heterozygous missense variants have been reported in multiple unrelated pedigrees with HCM, demonstrating segregation with disease and concordant functional effects. On this basis, the clinical validity of the MYL3–HCM association is Definitive.

1. Clinical Validity

The MYL3–HCM association is categorized as Definitive. Rationale: at least 8 unrelated probands carrying heterozygous MYL3 missense variants have been described across four independent families, with clear segregation in pedigrees and functional assay concordance ([PMID:22957257]).

2. Genetic Evidence (Strong)

Inheritance is autosomal dominant with incomplete and age-dependent penetrance. Segregation analyses identified 3 additional affected relatives harboring the p.Val79Ile variant in one large kindred ([PMID:22957257]). Case series and WES revealed 7 subjects with the recurrent c.281G>A (p.Arg94His) variant in two HCM cohorts ([PMID:26443374]). The variant spectrum includes missense substitutions distributed across the EF-hand domains, with recurrent alleles (e.g., p.Val79Ile, p.Arg94His, p.Glu177Gly).

3. Functional Evidence (Moderate)

Biochemical assays demonstrate that cardiomyopathic MYL3 variants alter actin-activated ATPase activity and increase Ca2+ sensitivity of thin-filament sliding (e.g., p.Glu177Gly, p.Glu56Gly) ([PMID:36509720]). Zebrafish morpholino knockdown of the orthologous gene supports essential light chain function and shows that human loss-of-function alleles fail to rescue cardiac contractility deficits ([PMID:33288880]).

4. Conflicting Evidence

A CRISPR/Cas9 iPSC model of the c.170C>A (p.Ala57Asp) variant showed no overt HCM phenotype, suggesting that not all rare MYL3 VUS exert pathogenic effects at the cellular level ([PMID:29914921]). This underscores variant-specific interpretation.

5. Integration & Conclusion

Overall, multiple heterozygous MYL3 missense variants causally contribute to HCM through altered myosin-actin interactions, supported by segregation and functional studies. Although recessive and benign alleles exist, the majority of AD missense variants yield a gain-of-function or dominant-negative effect. Additional deep-intronic or structural variants in MYL3 remain to be fully explored.

Key Take-Home: Genetic testing of MYL3 variants informs HCM diagnosis, risk stratification, and cascade screening for family members.

References

• Biochemistry research international • 2012 • A novel Myosin essential light chain mutation causes hypertrophic cardiomyopathy with late onset and low expressivity. PMID:22957257
• Journal of cardiology • 2016 • Whole exome sequencing combined with integrated variant annotation prediction identifies a causative myosin essential light chain variant in hypertrophic cardiomyopathy. PMID:26443374
• Biochemistry • 2022 • Properties of Cardiac Myosin with Cardiomyopathic Mutations in Essential Light Chains. PMID:36509720
• Genetics in medicine • 2021 • Autosomal recessive cardiomyopathy and sudden cardiac death associated with variants in MYL3. PMID:33288880

Evidence Based Scoring (AI generated)