Cardiomyopathy & Structural Heart

Deep intronic FBN1 variant associated with larger ascending aortic dimensions and elevated risk of thoracic aortic aneurysm and dissection through altered fibrillin-1 microfibril function and dysregulated TGF-β sequestration in the aortic wall

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

Rare pathogenic missense variant in cardiac alpha-tropomyosin causing familial hypertrophic cardiomyopathy through increased calcium sensitivity and impaired muscle relaxation

Pathogenic alpha-tropomyosin missense variant that increases thin filament calcium sensitivity, causing familial hypertrophic cardiomyopathy; a founder mutation accounting for ~6.5% of HCM cases in Finland

Missense variant in alpha-dystrobrevin disrupting the EF-hand calcium-binding domain, associated with left ventricular noncompaction cardiomyopathy in a single Japanese family

Rare pathogenic TTR missense variant causing hereditary transthyretin amyloidosis with predominantly central nervous system and oculoleptomeningeal involvement

Pathogenic nonsense variant in dystrophin creating a premature stop codon at position 3182, causing X-linked dilated cardiomyopathy and Duchenne/Becker muscular dystrophy with prominent cardiac involvement

Pathogenic missense variant in emerin that weakens nuclear lamina interactions, causing X-linked Emery-Dreifuss muscular dystrophy with progressive cardiac conduction defects and cardiomyopathy

Intronic FBN1 variant that requires two copies of the G allele to impair fibrillin-1's TGF-β1 sequestration, elevating aortic dissection risk in a recessive pattern

Rare pathogenic missense variant in desmoplakin that enhances calpain-mediated protein degradation, destabilizing the cardiac desmosome and causing biventricular arrhythmogenic cardiomyopathy with left ventricular predominance

Splice donor variant in plakophilin-2 that disrupts mRNA splicing at an exon–intron boundary, causing desmosomal haploinsufficiency and predisposing heterozygous carriers to arrhythmogenic right ventricular cardiomyopathy

Pathogenic truncating variant in cardiac myosin-binding protein C causing haploinsufficiency; heterozygous carriers develop hypertrophic cardiomyopathy through sarcomere dysfunction from reduced functional cMyBP-C levels

TGF-beta signaling regulator variant identified as the top shared locus between migraine and type 2 diabetes

Nonsense variant in dystrophin that eliminates full-length protein, causing X-linked dilated cardiomyopathy in males and significant carrier risk in females

Pathogenic missense variant in fibrillin-1 replacing the calcium-coordinating aspartate at position 1113 with glycine in an EGF-like calcium-binding domain, disrupting microfibril assembly and predisposing heterozygous carriers to familial thoracic aortic aneurysm and dissection (FTAAD) and Marfan syndrome

Rare pathogenic missense variant in junctophilin-2 that disrupts T-tubule/sarcoplasmic reticulum coupling and impairs calcium-induced calcium release, causing hypertrophic cardiomyopathy

Ultra-rare pathogenic missense variant in the C6 fibronectin domain of cardiac myosin-binding protein C that destabilizes domain folding and causes functional haploinsufficiency, leading to hypertrophic cardiomyopathy with early onset and high penetrance.

Pathogenic missense variant in fibrillin-1 replacing glycine 2627 with arginine in a calcium-binding EGF-like domain, disrupting microfibril assembly and predisposing heterozygous carriers to Marfan syndrome with aortic root dilation, lens dislocation, and skeletal overgrowth.

A rare missense variant in the C1 immunoglobulin domain of cardiac myosin-binding protein C, found in individuals with hypertrophic and dilated cardiomyopathy; classified as a variant of uncertain significance with conflicting evidence for independent pathogenicity

Pathogenic missense variant in cardiac alpha-actin that causes hypertrophic cardiomyopathy, left ventricular noncompaction, and septal defects through impaired sarcomeric force generation.

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

Rare pathogenic missense variant in DCHS1 (R2513H) causing mitral valve prolapse type 2 through loss of protein stability and disrupted planar cell polarity signaling during valve development

Intronic FBN1 variant associated with elevated thoracic aortic dissection risk through altered fibrillin-1 microfibril structure and TGF-β1 bioavailability

Pathogenic beta-myosin heavy chain missense variant causing a hypercontractile sarcomere; heterozygous carriers (CT) have high penetrance for hypertrophic cardiomyopathy and are at significant risk for sudden cardiac death and heart failure

Rare pathogenic missense variant at the last nucleotide of MYBPC3 exon 23, causing aberrant splicing and haploinsufficiency; strongly associated with hypertrophic cardiomyopathy (autosomal dominant)

Pathogenic missense variant in the myosin motor domain causing hypertrophic cardiomyopathy with a 47% lifetime atrial fibrillation rate in affected adults; requires family cardiac screening

Pathogenic missense variant in the C3 domain of cardiac myosin-binding protein C replacing arginine with tryptophan at position 502, disrupting sarcomeric protein-protein interactions and causing hypertrophic cardiomyopathy through an autosomal dominant mechanism.

Missense variant in MYH15 encoding a Thr1105Ala substitution in myosin heavy chain 15, associated with modest coronary heart disease and noncardioembolic stroke risk

Protein-truncating frameshift deletion in obscurin; homozygous or compound heterozygous carriers lose functional obscurin in muscle, predisposing to recurrent, exercise-triggered rhabdomyolysis.

Ultra-rare autosomal recessive MYBPC3 missense variant; homozygotes develop severe HCM while heterozygous carriers remain clinically unaffected up to age 71 in the single reported family

Rare pathogenic/likely pathogenic missense variant in the C5 immunoglobulin-like domain of cardiac myosin-binding protein C, disrupting sarcomere assembly and causing hypertrophic cardiomyopathy through haploinsufficiency (autosomal dominant)

Pathogenic missense variant in the beta-myosin heavy chain motor domain causing hypertrophic cardiomyopathy through a dominant-negative mechanism; documented in more than 15 unrelated HCM-affected individuals and absent from population databases

Ultra-rare TPM1 missense variant of uncertain significance found in hypertrophic cardiomyopathy panels; alters a residue where other pathogenic substitutions are known, but evidence is insufficient for definitive pathogenicity classification

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

Pathogenic missense variant in the regulatory myosin light chain gene; heterozygous carriers face substantially elevated risk of hypertrophic cardiomyopathy and warrant cardiac evaluation and cascade screening of first-degree relatives

Nonsense variant in desmoplakin that truncates the protein at codon 550, causing severe haploinsufficiency and predisposing heterozygous carriers to arrhythmogenic cardiomyopathy with predominantly left ventricular fibrosis and high arrhythmic risk

Rare truncating variant in desmoplakin that creates a premature stop codon at position 72, disrupting cardiac desmosomal integrity and predisposing carriers to arrhythmogenic cardiomyopathy with predominantly left ventricular involvement.

Rare missense variant in desmoplakin that likely disrupts desmosomal integrity and is associated with arrhythmogenic cardiomyopathy risk

Nonsense variant in desmoplakin that truncates the protein at codon 1277, causing haploinsufficiency and predisposing heterozygous carriers to arrhythmogenic cardiomyopathy with left ventricular fibrosis

Pathogenic DSP nonsense variant creating a premature stop codon at position 160 (p.Arg160Ter), causing desmoplakin haploinsufficiency and desmoplakin-associated arrhythmogenic cardiomyopathy with predominantly left ventricular fibrosis

Pathogenic stop-gain in desmoplakin's tail domain; one copy truncates the protein by 1,062 amino acids, disrupting desmosomal junctions in the heart and causing arrhythmogenic cardiomyopathy with left ventricular predominance

Pathogenic frameshift deletion in NOTCH1 causing haploinsufficiency; carriers face substantially elevated risk of bicuspid aortic valve, progressive aortic valve calcification and stenosis, and thoracic aortic aneurysm through loss of Notch-mediated suppression of osteoblastic calcification

Intronic variant in the myosin heavy chain 15 gene associated with impaired coronary microvascular function and abnormal coronary flow reserve in men (OR 2.27)

Pathogenic missense variant in junctophilin-2 that disrupts sarcoplasmic reticulum coupling and calcium signaling, causing hypertrophic cardiomyopathy with high age-dependent penetrance

Frameshift deletion in obscurin, a giant sarcomeric scaffold protein; heterozygous carriers have a moderately elevated risk of OBSCN-related cardiomyopathy, warranting cardiac surveillance.

Rare pathogenic missense variant in cardiac troponin T causing calcium desensitization and autosomal dominant dilated cardiomyopathy and left ventricular noncompaction

Most common amyloidogenic TTR variant in African Americans, causing late-onset hereditary transthyretin cardiac amyloidosis (hATTR-CM); now treatable with TTR stabilizers

Pathogenic missense variant in ACADM reducing MCAD enzyme activity, predisposing to fatty acid oxidation failure and cardiac stress during fasting, illness, or exercise