rs104894369 — MYL2 Arg58Gln

Pathogenic missense variant in the cardiac regulatory myosin light chain causing early-onset severe hypertrophic cardiomyopathy with high risk of sudden cardiac death

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MYL2 Arg58Gln — When the Heart's Throttle Jams

Every heartbeat depends on a finely tuned partnership between motor proteins and the regulatory machinery that controls them. One of those regulators is the ventricular regulatory myosin light chain11 ventricular regulatory myosin light chain
MYL2 (myosin light chain 2) is a 165-amino-acid protein that wraps around the neck region of the cardiac beta-myosin heavy chain. Its job is to modulate ATPase activity, calcium sensitivity, and the structural organization of myosin heads on the thick filament, encoded by MYL2. The Arg58Gln substitution — replacing a positively charged arginine with a neutral glutamine at position 58, near the calcium-binding EF-hand domain — is one of the original HCM-causing mutations identified in the MYL2 gene, and one of the most clinically consequential. It was classified as Pathogenic by ClinVar (VCV000218601) based on consistent evidence across multiple independent submitters, and is listed as OMIM allelic variant 160781.0004.

The Mechanism

Position 58 lies within a critical stretch of MYL2 that mediates calcium binding and phosphorylation-dependent regulation of the myosin motor. The Arg58Gln change abolishes calcium binding at the EF-hand domain — biochemical studies22 biochemical studies
Studies using recombinant R58Q-RLC protein confirmed that the mutant loses Ca²⁺ binding at physiological concentrations, whereas phosphorylation of the Ser15 residue can partially restore binding capacity demonstrate that the mutant form cannot bind Ca²⁺ at all under basal conditions.

At the thick-filament level, the consequence is counterintuitive: rather than driving hyperactivation as one might expect in HCM, Gollapudi et al., 201833 Gollapudi et al., 2018
Gollapudi SK et al., J Mol Cell Cardiol, 2018 — used membrane-permeabilized cardiac papillary muscle preparations and X-ray diffraction to assess filament structural state in R58Q conditions showed that R58Q stabilizes the myosin thick filament OFF state — the sequestered configuration where myosin heads are folded back against the thick filament and unavailable for actin interaction. This reduces the number of cross-bridges available during systole and uncouples length-dependent activation (the Frank-Starling mechanism). Phosphorylation of Ser15 on R58Q-RLC restores filament regulation and rescues length-dependent activation, pointing to impaired myosin light chain kinase (MLCK) phosphorylation as the central pathogenic mechanism.

The net result is a heart that cannot efficiently calibrate its own contraction to preload — diastolic dysfunction, compensatory hypertrophy, and ultimately arrhythmogenic remodeling. Patient-derived iPSC-cardiomyocytes44 iPSC-cardiomyocytes
Induced pluripotent stem cell-derived cardiomyocytes — heart cells grown in a dish from a patient's own skin or blood cells, reprogrammed to their embryonic state and then differentiated into beating cardiac muscle cells that carry the patient's exact genetic variants from an R58Q carrier were 30% larger than controls at 60 days, showed significantly higher rates of myofibrillar disarray and irregular beating, and had a 45% reduction in L-type calcium channel density — recapitulating the clinical features of apical HCM in a dish.

The Evidence

MYL2 Arg58Gln was first identified by Flavigny et al., 199855 Flavigny et al., 1998
Flavigny J et al., J Mol Med, 76:208–214, 1998 — screened 42 familial HCM probands using SSCP analysis and sequencing; identified R58Q in two families and Phe18Leu in one, establishing two novel pathogenic MYL2 variants in three unrelated HCM families. Affected individuals showed moderate asymmetric septal hypertrophy (Maron type 1 or 3) with a notably malignant course: early clinical onset and premature sudden cardiac death distinguishing R58Q from other MYL2 variants with more benign trajectories (e.g., Glu22Lys).

A systematic analysis of 186 unrelated HCM probands66 systematic analysis of 186 unrelated HCM probands
Kabaeva ZT et al., Eur J Hum Genet, 2002 — screened the full MYL2 and MYL3 coding sequences by SSCP and sequencing in a well-characterized European HCM cohort; confirmed R58Q in additional families with severe asymmetric hypertrophy confirmed R58Q in subsequent families and characterized the clinical spectrum, noting its association with the more malignant end of the MYL2 phenotype spectrum.

A four-generation Chinese HCM family77 four-generation Chinese HCM family
Yin et al., Mol Genet Genomics, 2019 — comprehensive clinical and genetic investigation of a large Chinese family; R58Q found in all six overtly affected members plus two clinically unaffected juveniles who later developed echocardiographic changes demonstrates that R58Q behaves as an autosomal dominant variant with high but age-dependent penetrance: young carriers can carry the mutation without overt LVH while already showing early structural changes on imaging. Three presumed carriers among deceased family members had died suddenly, underscoring the high SCD burden.

Phosphomimic rescue studies88 Phosphomimic rescue studies
Szekeres et al., Arch Biochem Biophys, 2019 — reconstituted porcine cardiac myofibrils with S15D-R58Q double-mutant RLC to mimic constitutive Ser15 phosphorylation; showed partial rescue of cross-bridge kinetics and myofilament mechanics showing that the S15D-R58Q phosphomimic rescues several aspects of contractile dysfunction in reconstituted preparations, providing proof-of-concept that targeting MLCK-mediated RLC phosphorylation could be therapeutic.

Practical Actions

Identifying an Arg58Gln carrier changes clinical management fundamentally. This is an autosomal dominant pathogenic variant — a single copy is sufficient for disease expression — with documented cases of sudden cardiac death before age 30. The 2024 AHA/ACC HCM guidelines explicitly include MYL2 among the eight core sarcomeric genes recommended for genetic testing in all HCM patients, and cascade testing in at-risk relatives is a Class I recommendation. For carriers:

The highest-priority action is confirming the cardiac phenotype (or absence of it) with imaging and arrhythmia monitoring. Young carriers may be pre-phenotypic but are already at risk. Formal SCD risk stratification determines ICD candidacy. Avoidance of competitive sports and high-intensity exertion is required pending evaluation — sudden cardiac death in HCM is heavily exercise-associated.

Interactions

R58Q's pathogenic mechanism intersects with MYL2 phosphorylation status: cardiac myosin light chain kinase (MLCK) phosphorylates Ser15 of MYL2 during exercise and sympathetic activation. In R58Q carriers, the diminished phosphorylation capacity at position 58 (a secondary phosphorylation site) impairs the cooperative regulation of the thick filament — meaning exercise-induced demands may disproportionately stress the heart in ways that do not resolve normally. This is likely part of the mechanism linking R58Q to exercise-triggered arrhythmic events.

Other sarcomeric HCM genes, including MYBPC3 (rs36211723, rs28933979), TPM1 (rs104894502), MYH7, TNNT2, and the related MYL2 G162E variant (rs397516406), can produce overlapping clinical phenotypes. Patients with two pathogenic sarcomeric variants ("double-positive HCM") tend to have more severe hypertrophy and earlier disease onset. The likelihood of compound sarcomeric genotypes is low given the individual rarity of each variant, but warrants consideration in patients with unusually severe or early-onset HCM.

Genotype Interpretations

What each possible genotype means for this variant.

GG No Arg58Gln Variant Normal

No MYL2 Arg58Gln — no elevated HCM risk from this variant

You carry two copies of the normal MYL2 allele at this position and do not have the Arg58Gln mutation. Your risk of hypertrophic cardiomyopathy from this specific variant is not elevated. Virtually everyone in the general population shares this result — Arg58Gln is absent from gnomAD population databases, consistent with it being a disease-causing variant under strong negative selection. Other sarcomeric gene variants (in MYBPC3, MYH7, TNNT2, and other MYL2 positions) can independently cause HCM and are not captured by this result.

AG Arg58Gln Carrier High Risk

Carries one copy of MYL2 Arg58Gln — pathogenic for early-onset hypertrophic cardiomyopathy

The MYL2 protein sits at the neck region of cardiac beta-myosin heavy chain, regulating ATPase activity and the structural organization of myosin heads on the thick filament. Position 58 lies in an EF-hand calcium-binding loop and near a secondary phosphorylation regulatory region. The Arg→Gln substitution (c.173G>A, NM_000432.4) removes the basic arginine residue and replaces it with uncharged glutamine, collapsing calcium coordination at this site and impairing cooperative regulation of the thick filament.

X-ray diffraction studies of cardiac papillary muscle showed that R58Q shifts the equilibrium of myosin heads toward the sequestered OFF state — paradoxically reducing available cross-bridges rather than increasing them. This decouples the Frank-Starling response (the heart's intrinsic mechanism for adjusting stroke volume to venous return) and imposes a chronic compensatory burden that drives hypertrophic remodeling. Long-term, the result is progressive left ventricular wall thickening, interstitial fibrosis, diastolic dysfunction, and an arrhythmogenic substrate.

Clinical presentations documented in published families include: - Asymmetric septal hypertrophy (Maron type 1 or 3) in heterozygotes - Diagnosis in childhood or early adulthood (one patient diagnosed at age 7) - Ventricular tachycardia progressing to ventricular fibrillation - ICD implantation in the second or third decade of life - Sudden cardiac death in multiple family members across generations

Penetrance is high but age-dependent — young adult carriers may lack obvious LVH while already showing subtle echocardiographic changes. Annual cardiac surveillance is recommended even in asymptomatic carriers.

AA Homozygous Arg58Gln Homozygous

Carries two copies of MYL2 Arg58Gln — severe HCM risk, essentially unobserved in general population

You carry two copies of the MYL2 Arg58Gln mutation, one on each chromosome 12. This is an exceptionally rare genotype — Arg58Gln is itself absent from gnomAD population databases, and homozygosity would require two carrier parents. No published homozygous Arg58Gln cases have been described in the medical literature. Based on analogous autosomal dominant HCM mutations, homozygosity is unlikely to be strictly dose-additive in terms of disease severity, but this is speculative. The management is the same as for AG heterozygous carriers — and potentially more urgent — with the added consideration that all biological children will inherit at least one copy of the variant.