Heart disease: genes and variants

Genes linked to Heart disease

• GATA4: Transcription factor GATA-4

  It controls cardiac development and adult cardiac gene expression and also contributes to gonadal and gastrointestinal development. Heterozygous pathogenic variants can cause congenital heart defects, particularly septal defects, and occasionally cardiomyopathy or disorders of sex development.

  4 ClinVar pathogenic / likely pathogenic and 0 uncertain variants in GATA4 have source records linked to Heart disease. Association strength is not clinical gene validity.

• NKX2-5: Homeobox protein Nkx-2.5

  It specifies myocardial lineages and maintains genes needed for adult conduction and contractile function. Heterozygous pathogenic variants can cause congenital heart defects, especially atrial septal defects, often with progressive conduction disease.

  2 ClinVar pathogenic / likely pathogenic and 1 uncertain variants in NKX2-5 have source records linked to Heart disease. Association strength is not clinical gene validity.

• ABL1: Tyrosine-protein kinase ABL1

  It coordinates cytoskeletal remodeling, adhesion, DNA-damage responses, and growth signaling through tightly regulated tyrosine phosphorylation. Fusion with BCR removes normal control and creates the constitutively active kinase that drives chronic myeloid leukemia and subsets of acute lymphoblastic leukemia.

  1 ClinVar pathogenic / likely pathogenic and 0 uncertain variants in ABL1 have source records linked to Heart disease. Association strength is not clinical gene validity.

• MECOM: Histone-lysine N-methyltransferase MECOM

  Its EVI1-containing transcriptional programs regulate hematopoietic stem-cell self-renewal and differentiation. Rearrangement or overexpression is a potent adverse-risk driver in myeloid malignancies, while germline variants can cause congenital bone-marrow failure and developmental syndromes.

  1 ClinVar pathogenic / likely pathogenic and 0 uncertain variants in MECOM have source records linked to Heart disease. Association strength is not clinical gene validity.

• PTPN11: Tyrosine-protein phosphatase non-receptor type 11

  Its SHP2 phosphatase activity promotes RAS-MAPK signaling downstream of many receptor tyrosine kinases and cytokine receptors. Germline dysregulating variants cause Noonan-spectrum disorders, while somatic activating variants drive juvenile myelomonocytic leukemia and other cancers.

  1 ClinVar pathogenic / likely pathogenic and 0 uncertain variants in PTPN11 have source records linked to Heart disease. Association strength is not clinical gene validity.

• RIT1: GTP-binding protein Rit1

  It transmits growth and stress signals through RAS-MAPK and related pathways and is important in cardiovascular and nervous-system development. Germline activating variants cause Noonan syndrome, often with a high frequency of hypertrophic cardiomyopathy.

  1 ClinVar pathogenic / likely pathogenic and 0 uncertain variants in RIT1 have source records linked to Heart disease. Association strength is not clinical gene validity.

• F2: Prothrombin

  After cleavage to thrombin, it converts fibrinogen to fibrin and activates multiple additional coagulation components to amplify clot formation. Deficiency can cause bleeding, whereas the common G20210A variant raises prothrombin levels and increases venous-thrombosis risk.

  0 ClinVar pathogenic / likely pathogenic and 0 uncertain variants in F2 have source records linked to Heart disease. Association strength is not clinical gene validity.

• LDLR: Low-density lipoprotein receptor

  It removes ApoB-containing LDL particles from the circulation through receptor-mediated endocytosis, especially in hepatocytes. Loss-of-function variants are the most common cause of familial hypercholesterolemia and lead to lifelong LDL elevation and premature atherosclerotic disease.

  0 ClinVar pathogenic / likely pathogenic and 0 uncertain variants in LDLR have source records linked to Heart disease. Association strength is not clinical gene validity.

• LPA: Apolipoprotein(a)

  Its apolipoprotein(a) component covalently attaches to an LDL-like particle to form lipoprotein(a), whose circulating level is largely genetically determined. High Lp(a) is a causal risk factor for atherosclerotic cardiovascular disease and calcific aortic-valve disease.

  0 ClinVar pathogenic / likely pathogenic and 0 uncertain variants in LPA have source records linked to Heart disease. Association strength is not clinical gene validity.

• PCSK9: Proprotein convertase subtilisin/kexin type 9

  By binding hepatic LDL receptors and promoting their lysosomal degradation, it reduces receptor recycling and raises circulating LDL cholesterol. Gain-of-function variants cause autosomal dominant hypercholesterolemia, whereas loss-of-function variants lower LDL cholesterol and cardiovascular risk.

  0 ClinVar pathogenic / likely pathogenic and 0 uncertain variants in PCSK9 have source records linked to Heart disease. Association strength is not clinical gene validity.

• PLCG2: 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-2

  It generates IP3 and diacylglycerol downstream of immune receptors, triggering intracellular calcium release and protein-kinase-C signaling in B cells and myeloid cells. Gain-of-function variants cause autoinflammatory and antibody-deficiency syndromes, while somatic mutations can mediate resistance to BTK inhibitors.

  0 ClinVar pathogenic / likely pathogenic and 0 uncertain variants in PLCG2 have source records linked to Heart disease. Association strength is not clinical gene validity.

• PROS1: Vitamin K-dependent protein S

  It serves as an essential cofactor for activated protein C and also participates in TAM-receptor signaling involved in clearance of apoptotic cells. Heterozygous deficiency increases susceptibility to venous thrombosis, while severe deficiency can cause neonatal purpura fulminans.

  0 ClinVar pathogenic / likely pathogenic and 0 uncertain variants in PROS1 have source records linked to Heart disease. Association strength is not clinical gene validity.

• TTN: Titin

  Its enormous titin polypeptide spans much of the sarcomere and provides passive elasticity, structural alignment, and mechanosensing in striated muscle. Truncating variants are among the most common genetic causes of dilated cardiomyopathy, while other variants cause diverse skeletal and cardiac myopathies.

  0 ClinVar pathogenic / likely pathogenic and 0 uncertain variants in TTN have source records linked to Heart disease. Association strength is not clinical gene validity.

• MYL2: Myosin regulatory light chain 2, ventricular/cardiac muscle isoform

  It modulates cardiac myosin-head mechanics and phosphorylation-dependent force generation in ventricular sarcomeres. Pathogenic variants are an established cause of familial hypertrophic cardiomyopathy and can also produce other cardiomyopathy phenotypes.

  1 ClinVar pathogenic / likely pathogenic and 0 uncertain variants in MYL2 have source records linked to Heart disease. Association strength is not clinical gene validity.

Weakly linked (only a few uncertain records): ACVR1, CTNNB1, FOXP1, GATA5, MYH6 and SOS2.

ClinVar pathogenic and likely pathogenic variants linked to Heart disease

Which prediction tools work for Heart disease

Observed separation of ClinVar pathogenic / likely pathogenic from benign / likely benign variants (AUROC × 100). This benchmark is not a clinical recommendation.

• CATVariant: 83 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• PolyPhen-2: 82 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• SIFT: 71 out of 100

Same protein, different disease

• Atrioventricular septal defect 4 also has ClinVar records linked to GATA4 variants; they fall mostly in different places as the Heart disease variants (7 pathogenic / likely pathogenic).
• Atrial septal defect also has ClinVar records linked to GATA4 variants; they fall mostly in different places as the Heart disease variants (5 pathogenic / likely pathogenic).
• Testicular anomalies with or without congenital heart disease also has ClinVar records linked to GATA4 variants; they fall mostly in different places as the Heart disease variants (3 pathogenic / likely pathogenic).
• Atrial septal defect also has ClinVar records linked to NKX2-5 variants; they fall mostly in different places as the Heart disease variants (14 pathogenic / likely pathogenic).
• Noonan syndrome also has ClinVar records linked to RIT1 variants; they fall partly in the same places as the Heart disease variants (22 pathogenic / likely pathogenic).
• Noonan syndrome and Noonan-related syndrome also has ClinVar records linked to RIT1 variants; they fall mostly in different places as the Heart disease variants (9 pathogenic / likely pathogenic).
• RASopathy also has ClinVar records linked to RIT1 variants; they fall mostly in different places as the Heart disease variants (5 pathogenic / likely pathogenic).
• Congenital heart defects and skeletal malformations syndrome also has ClinVar records linked to ABL1 variants; they fall mostly in different places as the Heart disease variants (14 pathogenic / likely pathogenic).
• Leukemia, Philadelphia chromosome-positive, resistant to imatinib also has ClinVar records linked to ABL1 variants; they fall mostly in different places as the Heart disease variants (5 pathogenic / likely pathogenic).
• Chronic myeloid leukemia also has ClinVar records linked to ABL1 variants; they fall mostly in different places as the Heart disease variants (3 pathogenic / likely pathogenic).
• Radioulnar synostosis with amegakaryocytic thrombocytopenia 2 also has ClinVar records linked to MECOM variants; they fall mostly in different places as the Heart disease variants (5 pathogenic / likely pathogenic).
• Radioulnar synostosis also has ClinVar records linked to MECOM variants; they fall mostly in different places as the Heart disease variants (4 pathogenic / likely pathogenic).
• RASopathy also has ClinVar records linked to PTPN11 variants; they fall mostly in different places as the Heart disease variants (51 pathogenic / likely pathogenic).
• Noonan syndrome also has ClinVar records linked to PTPN11 variants; they fall mostly in different places as the Heart disease variants (44 pathogenic / likely pathogenic).
• Noonan syndrome and Noonan-related syndrome also has ClinVar records linked to PTPN11 variants; they fall mostly in different places as the Heart disease variants (29 pathogenic / likely pathogenic).
• LEOPARD syndrome 1 also has ClinVar records linked to PTPN11 variants; they fall mostly in different places as the Heart disease variants (16 pathogenic / likely pathogenic).
• Metachondromatosis also has ClinVar records linked to PTPN11 variants; they fall mostly in different places as the Heart disease variants (11 pathogenic / likely pathogenic).

Diseases related to Heart disease

• Myocardial infarction, also linked to LDLR, LPA and PCSK9
• Familial hypercholesterolemia, also linked to LDLR and PCSK9
• Hypertrophic cardiomyopathy, also linked to MYL2 and TTN
• RASopathy, also linked to PTPN11 and RIT1
• Noonan syndrome, also linked to PTPN11 and RIT1
• Noonan syndrome and Noonan-related syndrome, also linked to PTPN11 and RIT1
• Cardiomyopathy, also linked to MYL2 and TTN
• Atrial septal defect, also linked to GATA4 and NKX2-5
• Homozygous familial hypercholesterolemia, also linked to LDLR and PCSK9
• Microcephaly, also linked to ABL1 and PTPN11
• Ventricular septal defect, also linked to GATA4 and NKX2-5
• Alzheimer disease, also linked to PLCG2

Frequently asked questions

Which genes have records linked to Heart disease?

This view contains 14 analyzed proteins: GATA4, NKX2-5, ABL1, MECOM, PTPN11 and 9 more. Links come from clinical records and association databases. They do not imply that every listed gene is a validated cause, and missing genes may not yet be analyzed.

What do the clinical classifications mean?

Linked records include 11 pathogenic or likely pathogenic variants, 5 variants of uncertain significance and 3 with conflicting classifications. Labels summarize source records; multi-condition records may not make a separate assertion for this disease. Check the original record and review status.

Does the evidence score change a VUS classification?

No. 0 VUS or conflicting variants reach the likely-pathogenic points range on the computable criteria available here. This is a research prioritization signal, not a clinical classification. Patient, family and other required evidence may be missing.

Can I download the variant evidence?

Download the CSV for all 24 variants in the selected disease scope, including clinical labels, review status, evidence criteria, predictor scores, functional measurements and population frequency where available.

About this data

Variant–disease links come from ClinVar, Open Targets and UniProt, pooled from eligible public CATVariant analyses of each human protein. Evidence scores use the ACMG/AMP Bayesian points scale with computable criteria only (position among known disease variants, rarity in gnomAD, calibrated predictors, deep mutational scanning); there is no family or patient data, so they prioritise variants for expert review and never classify them.

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