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

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

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

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

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

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

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

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

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

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

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