ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000011.9) (NC_000011.10)
  • Haploinsufficiency score: 1
  • Strength of Evidence (disclaimer): Little evidence for dosage pathogenicity
Evidence for haploinsufficiency phenotype
PubMed ID Description
26258302 Durst et al (2015) describe pathogenic variants in DCHS1 identified in families with non-syndormic mitral valve prolapse (MVP). Linkage analysis of the first family previously identified in Freed et al (PMID: 12707861) demonstrated a candidate region for MVP at 11p15.4. Four affected individuals from this family were sequenced within the target region, and all demonstrated a compound heterozygous missense variants in DCSH1 in cis, p.P197L and p.R2513H, segregating with the phenotype. Western blots from transfected constructs created with individual p.P197L and p.R2513H variants demonstrated the p.R2513H variant resulted in reduced protein levels, consistent with loss-of-function. Two additional MVP families were identified by exome sequencing, both of which had the same heterozygous missense variant, c.6988C>T (p.R2330C) segregating with the phenotype. Western blot analyses demonstrated an apparent loss of function mechanism for this variant.

Haploinsufficiency phenotype comments:

PMID: 29224215 Clemenceau et al evaluated 100 asymptomatic subjects with MVP and mitral valve regurgitation for the specific variants in DCHS1 reported by Durst et al. None of the 100 had either variant. However, two of the 100 subjects were found to have predicted pathogenic missense variants in exon 21: p.R2462Q and p.A2464P. Further sequencing of all 21 exons and the UTRs in 12 randomly selected subjects revealed potentially 4 additional deleterious missense variants (p.S415R, p.R2827P, p.A2867T, and p.R2770Q), which were then used for targeted screening in the remaining 88 subjects. In total, 24/100 subjects were identified with a likely pathogenic missense variant. The authors acknowledge that other variants not targeted may be present in the 88 subjects who were not fully sequenced. No functional studies were performed to determine the mechanism of pathogenicity of any variant in the study. Based on a lack of focal copy number changes in the literature and only one report with functional studies demonstrating possible haploinsufficiency, the current score for haploinsufficiency is 1.

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