ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000010.10) (NC_000010.11)
  • Haploinsufficiency score: 1
  • Strength of Evidence (disclaimer): Little evidence for dosage pathogenicity
Evidence for haploinsufficiency phenotype
PubMed ID Description
19064609 Mohapatra et al. (2009) described four different missense variants, one in-frame insertion/deletion and two conserved splice site variants in 14 unrelated subjects (14/269, 5.2%) with heterotaxy and/or isolated cardiovascular malformations. Two missense changes were also found in controls and two were inherited from normal parents. The authors report that "Functional analyses demonstrate that the missense variant forms of NODAL exhibit significant impairment of signaling as measured by decreased Cripto (TDGF-1) co-receptor-mediated activation of artificial reporters. Expression of these NODAL proteins also led to reduced induction of Smad2 phosphorylation and impaired Smad2 nuclear import. Taken together, these results support a role for mutations and rare deleterious variants in NODAL as a cause for sporadic human LR patterning defects." The splicing variants were not assessed with the functional assays and there is no information provided about whether aberrant splicing would lead to an in-frame or out-of-frame transcript.

Haploinsufficiency phenotype comments:

Changes in NODAL have been associated with heterotaxy and other congenital heart defects. While there are sequence changes at invariant splice sites reported in these patients, many have been inherited from healthy parents, functional assays of these changes have not been performed, and the consequence of these change on the transcript and any resulting protein are not clear. Therefore, a haploinsufficiency rating of 1, to indicate emerging evidence, seemed the most appropriate. Also of note: Sun et al. (2012) sequenced NODAL in 800 Chinese patients with nonsyndromic congenital heart disease and found 2 novel nonsynonymous missense variants (PMID: 22352765). No functional studies were performed. Roessler et al. (2009) also report various missense mutations and one splice mutation amongst individuals with CHD, laterality defects, and/or holoprosencephaly (PMID: 19553149). Functional assays of the missense changes only showed reduced luciferase expression but so did assays using very common polymorphisms. De Luca et al. (2010, PMID:19933292) report a patient with transposition of the great arteries and a splice mutation inherited from a healthy mother. This patient also had two missense mutations in cis in the CFC1 gene inherited from a healthy father.

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity