Atrial septal defect: genes and variants

Genes linked to Atrial septal defect

• 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.

  14 disease-causing and 230 uncertain variants in NKX2-5 are linked to Atrial septal defect.

• ACTC1: Actin, alpha cardiac muscle 1

  Its cardiac alpha-actin filaments form the core of the sarcomeric thin filament and provide the track against which myosin generates force. Pathogenic variants can cause hypertrophic or dilated cardiomyopathy and selected congenital heart defects.

  10 disease-causing and 172 uncertain variants in ACTC1 are linked to Atrial septal defect.

• 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.

  5 disease-causing and 11 uncertain variants in GATA4 are linked to Atrial septal defect.

• TBX20: T-box transcription factor TBX20

  It controls transcriptional programs required for cardiac chamber formation, septation, conduction-system development, and adult myocardial function. Heterozygous pathogenic variants can cause congenital heart defects and dilated cardiomyopathy.

  2 disease-causing and 23 uncertain variants in TBX20 are linked to Atrial septal defect.

• MYH6: Myosin-6

  Its alpha-myosin motor contributes to ATP-dependent force generation in the cardiac sarcomere, particularly in atrial myocardium. Pathogenic variants can cause cardiomyopathy, congenital heart defects, and selected conduction-system disorders.

  1 disease-causing and 77 uncertain variants in MYH6 are linked to Atrial septal defect.

• ABCC8: ATP-binding cassette sub-family C member 8

  It senses cellular nucleotide levels as the regulatory component of pancreatic beta-cell ATP-sensitive potassium channels and thereby couples glucose metabolism to insulin secretion. Loss-of-function variants cause congenital hyperinsulinism, whereas activating variants can cause neonatal diabetes.

  1 disease-causing and 0 uncertain variants in ABCC8 are linked to Atrial septal defect.

• GATA6: Transcription factor GATA-6

  It regulates developmental programs in the pancreas, heart, gut, and other endoderm-derived tissues. Haploinsufficiency is a major cause of pancreatic agenesis and neonatal diabetes and can also produce congenital heart disease and other developmental abnormalities.

  0 disease-causing and 10 uncertain variants in GATA6 are linked to Atrial septal defect.

• TGFB2: Transforming growth factor beta-2 proprotein

  Its secreted signaling regulates extracellular matrix, cell differentiation, proliferation, and cardiovascular development. Haploinsufficiency causes a Loeys-Dietz-spectrum connective-tissue disorder with increased risk of thoracic aortic aneurysm and dissection.

  1 disease-causing and 0 uncertain variants in TGFB2 are linked to Atrial septal defect.

• TPM1: Tropomyosin alpha-1 chain

  It lies along actin filaments and helps control access of myosin to actin in response to troponin and calcium, while also stabilizing cytoskeletal actin in nonmuscle cells. Pathogenic variants can cause hypertrophic or dilated cardiomyopathy and several congenital myopathies.

  1 disease-causing and 0 uncertain variants in TPM1 are linked to Atrial septal defect.

Weakly linked (only a few uncertain records): CREBBP and TBX5.

Where Atrial septal defect variants cluster

• NKX2-5 Homeobox (positions 138–197): 11 of 14 disease-causing changes, 4.2× more than its size predicts.

Known disease-causing variants in Atrial septal defect

Uncertain variants in Atrial septal defect that look disease-causing

Which prediction tools work for Atrial septal defect

How often each tool ranks a disease-causing variant above a harmless one (AUROC × 100).

• MetaLR: 95 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CATVariant: 95 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• MutPred2: 85 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• SIFT: 85 out of 100
• AlphaMissense: 84 out of 100
• PolyPhen-2: 74 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• EVE: 72 out of 100

Same protein, different disease

• Atrioventricular septal defect 4 is also caused by GATA4 variants; they fall partly in the same places as the Atrial septal defect variants (7 disease-causing).
• Hypertrophic cardiomyopathy is also caused by TPM1 variants; they fall mostly in different places as the Atrial septal defect variants (15 disease-causing).
• Primary dilated cardiomyopathy is also caused by TPM1 variants; they fall mostly in different places as the Atrial septal defect variants (6 disease-causing).
• Dilated cardiomyopathy is also caused by TPM1 variants; they fall mostly in different places as the Atrial septal defect variants (6 disease-causing).
• Loeys-Dietz syndrome is also caused by TGFB2 variants; they fall mostly in different places as the Atrial septal defect variants (6 disease-causing).
• Familial thoracic aortic aneurysm and aortic dissection is also caused by TGFB2 variants; they fall mostly in different places as the Atrial septal defect variants (5 disease-causing).

Diseases related to Atrial septal defect

• Hypertrophic cardiomyopathy, also linked to ACTC1, MYH6 and TPM1
• Dilated cardiomyopathy, also linked to ACTC1, TBX20 and TPM1
• Primary dilated cardiomyopathy, also linked to ACTC1, MYH6 and TPM1
• Familial isolated dilated cardiomyopathy, also linked to ACTC1, MYH6 and TPM1
• Monogenic diabetes, also linked to ABCC8 and GATA6
• Left ventricular noncompaction, also linked to ACTC1 and TPM1
• Atrioventricular septal defect 4, also linked to GATA4 and GATA6
• Ventricular septal defect, also linked to GATA4 and NKX2-5
• Hypoplastic left heart syndrome, also linked to MYH6 and NKX2-5
• Familial thoracic aortic aneurysm and aortic dissection, also linked to TGFB2
• Ehlers-Danlos syndrome, also linked to TGFB2
• Maturity-onset diabetes of the young, also linked to ABCC8

Frequently asked questions

Which genes are linked to Atrial septal defect?

In CATVariant, Atrial septal defect is linked to 9 analyzed proteins: NKX2-5 (Homeobox protein Nkx-2.5), ACTC1 (Actin, alpha cardiac muscle 1), GATA4 (Transcription factor GATA-4), TBX20 (T-box transcription factor TBX20), MYH6 (Myosin-6), ABCC8 (ATP-binding cassette sub-family C member 8) and 3 more.

How many genetic variants are linked to Atrial septal defect?

613 variants: 35 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 523 are of uncertain significance or have conflicting reports.

Which uncertain variants in Atrial septal defect look disease-causing?

2 uncertain variants reach the likely-pathogenic range of the ACMG/AMP points scale on computable evidence, for example ACTC1 A333V and NKX2-5 R189Q. These are leads for expert review, not diagnoses.

Which variant effect predictor works best for Atrial septal defect?

Among tools not trained on clinical labels, SIFT separates this disease's known disease-causing variants from harmless ones best (AUROC 0.85, based on 18 disease-causing and 286 harmless variants).

About this data

Variant–disease links come from ClinVar, Open Targets and UniProt, pooled from the latest public CATVariant analysis 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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