Aortic valve disease 2: genes and variants

Genes linked to Aortic valve disease 2

• TBX5: T-box transcription factor TBX5

  It directs upper-limb and cardiac developmental programs and later helps maintain cardiac conduction gene expression. Haploinsufficiency causes Holt-Oram syndrome, characterized by radial-ray limb abnormalities and congenital heart or conduction defects.

  9 disease-causing and 121 uncertain variants in TBX5 are linked to Aortic valve disease 2.

• NOTCH1: Neurogenic locus notch homolog protein 1

  Ligand-dependent cleavage releases an intracellular domain that directly controls transcriptional programs governing cell fate and differentiation. Pathogenic variants can cause congenital aortic-valve disease and left-sided heart defects, while activating or inactivating somatic changes contribute to several cancers.

  1 disease-causing and 182 uncertain variants in NOTCH1 are linked to Aortic valve disease 2.

Weakly linked (only a few uncertain records): TBX20.

Where Aortic valve disease 2 variants cluster

• TBX5 T-box (positions 58–238): 7 of 9 disease-causing changes, 2.2× more than its size predicts.

Known disease-causing variants in Aortic valve disease 2

Which prediction tools work for Aortic valve disease 2

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

• CATVariant: 94 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• MetaLR: 92 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• SIFT: 86 out of 100
• PolyPhen-2: 80 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• MutPred2: 78 out of 100 (learned from overlapping clinical labels, so this is optimistic)

Same protein, different disease

• Holt-Oram syndrome is also caused by TBX5 variants; they fall mostly in different places as the Aortic valve disease 2 variants (13 disease-causing).
• Adams-Oliver syndrome is also caused by NOTCH1 variants; they fall mostly in different places as the Aortic valve disease 2 variants (9 disease-causing).

Diseases related to Aortic valve disease 2

• Familial thoracic aortic aneurysm and aortic dissection, also linked to NOTCH1
• Connective tissue disorder, also linked to NOTCH1
• Holt-Oram syndrome, also linked to TBX5
• Adams-Oliver syndrome, also linked to NOTCH1
• Familial atrioventricular septal defect, also linked to TBX5

Frequently asked questions

Which genes are linked to Aortic valve disease 2?

In CATVariant, Aortic valve disease 2 is linked to 2 analyzed proteins: TBX5 (T-box transcription factor TBX5) and NOTCH1 (Neurogenic locus notch homolog protein 1).

How many genetic variants are linked to Aortic valve disease 2?

357 variants: 10 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 304 are of uncertain significance or have conflicting reports.

Which uncertain variants in Aortic valve disease 2 look disease-causing?

None of the uncertain variants currently reaches the likely-pathogenic range on computable evidence alone.

Which variant effect predictor works best for Aortic valve disease 2?

Among tools not trained on clinical labels, SIFT separates this disease's known disease-causing variants from harmless ones best (AUROC 0.86, based on 10 disease-causing and 275 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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