rs397516406 — MYL2 G162E (Gly162Glu)

MYL2 G162E — A Rare but Serious Cause of Familial Hypertrophic Cardiomyopathy

The heart's pumping force is generated by the sarcomere¹¹ sarcomere
the basic contractile unit of cardiac muscle, made of interdigitating thick and thin filaments, a precisely organized molecular motor. The MYL2 gene encodes the ventricular regulatory myosin light chain (RLC), a small protein that wraps around the neck of beta-myosin heavy chain and modulates the force and speed of cardiac contraction. The rs397516406 variant substitutes glutamic acid (a charged amino acid) for glycine (the smallest, most flexible amino acid) at position 162 of the protein — a region critical for calcium-dependent regulation of myosin motor activity. This change was classified as likely pathogenic for hypertrophic cardiomyopathy²² classified as likely pathogenic for hypertrophic cardiomyopathy
ClinVar variation ID 43479, reviewed by expert panel and is absent from the gnomAD database of over 187,000 population controls, consistent with a rare disease-causing variant rather than a benign polymorphism.

The Mechanism

The regulatory myosin light chain controls cardiac muscle contraction through two key mechanisms: it stabilizes the myosin lever arm (the structural domain that converts ATP hydrolysis into mechanical force), and it responds to calcium-dependent phosphorylation³³ calcium-dependent phosphorylation
phosphorylation of the RLC at Ser15 by myosin light chain kinase increases cross-bridge cycling rate and force production that tunes contractile output to cardiac demand. Position 162 sits within the C-terminal EF-hand domain⁴⁴ C-terminal EF-hand domain
a calcium-binding structural motif common to many regulatory proteins of the RLC. Replacing the tiny, conformationally flexible glycine with a bulky charged glutamic acid at this position is predicted to disrupt the local protein architecture and alter how the RLC interacts with the myosin neck. The downstream consequence — as with most sarcomeric HCM mutations — is hypercontractility and disordered calcium handling⁵⁵ hypercontractility and disordered calcium handling
sarcomere mutations increase myosin-actin cross-bridge stability, slowing relaxation and raising resting force, which over years drives the hypertrophic remodeling and fibrosis characteristic of HCM.

The Evidence

The pathogenicity of the G162E variant was established by Renaudin et al. (2018)⁶⁶ Renaudin et al. (2018)
Mol Diagn Ther 2018 Apr;22(2):219-223 through family segregation analysis. Among 27 family members of the index patient — a 51-year-old woman diagnosed with HCM — 16 carried the MYL2 p.Gly162Glu variant. Twelve of these 16 carriers (75%) had clinical evidence of cardiomyopathy, while none of the 11 non-carriers were affected. This cosegregation pattern is strong evidence for dominant pathogenicity and documents that penetrance is high but incomplete, with some carriers remaining subclinical or developing disease later in life.

MYL2 mutations as a group are a rare but recognized cause of HCM⁷⁷ a rare but recognized cause of HCM
accounting for approximately 1% of all genotype-positive HCM cases. The clinical consequences of sarcomere-positive HCM are serious. In Olivotto et al.'s 2008 cohort of 203 HCM patients⁸⁸ Olivotto et al.'s 2008 cohort of 203 HCM patients
Mayo Clin Proc 2008 Jun;83(6):630-638, mutation-positive patients experienced major adverse cardiovascular events (death, stroke, progression to advanced heart failure) at a rate of 25% versus 7% in mutation-negative patients over 4 years of follow-up (hazard ratio 4.27, p=.008). Critically, adverse events in the sarcomere-positive group occurred across all ages from 14 to 86 years, while mutation-negative patients were largely protected until after age 65. Other MYL2 variants illustrate the range of severity: Arg58Gln has been linked to premature sudden cardiac death in affected families⁹⁹ premature sudden cardiac death in affected families
early-onset disease with fatal arrhythmias in young adults, while Glu22Lys follows a more benign course.

Practical Actions

For carriers of the G162E variant, cardiac surveillance is the cornerstone of management¹⁰¹⁰ cardiac surveillance is the cornerstone of management
regular echocardiography detects structural changes before symptoms emerge, enabling earlier intervention. Annual or biennial echocardiography with assessment of left ventricular wall thickness, outflow tract gradient, and diastolic function allows longitudinal monitoring for HCM progression. Holter monitoring or cardiac event recording can detect subclinical arrhythmias — atrial fibrillation and non-sustained ventricular tachycardia are common in HCM and alter management thresholds for anticoagulation and defibrillator implantation. Patients who develop obstructive HCM (resting or provoked left ventricular outflow tract gradient ≥30 mmHg) may benefit from medical therapy with beta-blockers or disopyramide; septal reduction therapy (alcohol ablation or surgical myectomy) addresses severe refractory obstruction.

Because G162E follows autosomal dominant inheritance, each first-degree relative (parent, sibling, child) has a 50% probability of carrying the variant. Cascade genetic testing of first-degree relatives is the most efficient way to identify at-risk family members before they develop the structural changes that trigger symptoms and sudden cardiac death risk.

Interactions

MYL2 G162E acts as an autosomal dominant variant — a single copy is sufficient to cause disease. The risk does not compound with another copy of the same variant, though HCM severity can be modulated by additional variants in other sarcomeric genes (MYH7, MYBPC3, TNNT2, TNNI3). Individuals found to carry two or more sarcomeric gene mutations have been shown in clinical cohorts to face markedly elevated risk of end-stage progression and ventricular arrhythmias¹¹¹¹ markedly elevated risk of end-stage progression and ventricular arrhythmias
triple mutation carriers in the Girolami 2010 JACC study often required ICD or transplantation by their fourth decade. Comprehensive panel testing is recommended at the time of diagnosis.