rs397516406 — MYL2 G162E (Gly162Glu)

Pathogenic missense variant in the ventricular regulatory myosin light chain gene causing familial hypertrophic cardiomyopathy with ~75% penetrance

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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.

Genotype Interpretations

What each possible genotype means for this variant.

CC Non-carrier Normal

No MYL2 G162E variant detected

You do not carry the MYL2 p.Gly162Glu (G162E) variant. This ultra-rare pathogenic variant is absent in population databases (not observed in over 187,000 individuals across diverse ancestries in gnomAD), so non-carrier status is the expected result for the vast majority of people. This result does not rule out other genetic causes of hypertrophic cardiomyopathy — over 1,500 HCM-associated variants exist across more than 11 sarcomeric genes.

CT Carrier Carrier

Carrier of the MYL2 G162E pathogenic variant — cardiac surveillance indicated

The MYL2 regulatory myosin light chain (RLC) modulates the force and speed of cardiac muscle contraction. The G162E substitution — replacing the smallest amino acid (glycine) with a bulky charged one (glutamic acid) at a structurally critical position — is predicted to disrupt the RLC's interaction with the myosin motor domain, altering cross-bridge cycling dynamics. Over years, this molecular dysfunction drives the pathological myocyte hypertrophy, disarray, and fibrosis that define HCM.

The variant is documented in ClinVar (variation ID 43479) as likely pathogenic for HCM, with expert panel review. Population databases show zero instances of this variant among 187,186 controls, consistent with a rare disease allele rather than a common polymorphism. The Renaudin 2018 pedigree study identified 75% penetrance — meaning roughly three in four carriers will develop detectable HCM over their lifetime, with the remaining ~25% either subclinically affected or not yet manifesting at time of study.

Sarcomere-positive HCM carries a significantly worse prognosis than sarcomere-negative HCM. In Olivotto et al.'s cohort, sarcomere-positive patients were four times more likely to reach major adverse cardiovascular endpoints, and did so across all age groups — underscoring the importance of lifelong surveillance rather than age-limited screening.

TT Homozygous Homozygous

Homozygous for MYL2 G162E — urgent cardiac evaluation required

Homozygosity for autosomal dominant HCM-causing sarcomere mutations is rarely documented in the literature because both parents would need to be carriers of the same rare variant. For most dominant sarcomere mutations, homozygotes do not uniformly show more severe disease than heterozygotes — some studies report similar phenotypes, suggesting the dominant-negative mechanism is already maximal with one copy. However, the clinical course can still be serious, and the combination of two altered MYL2 alleles producing only mutant RLC protein cannot be assumed equivalent to heterozygosity without direct evidence for this specific variant.

Given that no population controls carry even one copy of this variant (gnomAD allele frequency of zero across 374,372 alleles), homozygosity would represent an extremely unusual genotype. Immediate specialist evaluation is the only appropriate response.