ClinGen Dosage Sensitivity Curation Page


Curation Status: Complete

Gene Information

Location Information

Evidence for Loss Phenotypes

Evidence for loss of function 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.

Evidence for Triplosenstive Phenotype

NOTE:The loss of function score should be used to evaluate deletions, and the triplosensitivity score should be used to evaluated duplications. CNVs encompassing more than one gene must be evaluated in their totality (e.g. overall size, gain vs. loss, presence of other genes, etc). The rating of a single gene within the CNV should not necessarily be the only criteria by which one defines a clinical interpretation. Individual interpretations must take into account the phenotype described for the patient as well as issues of penetrance and expressivity of the disorder. ACMG has published guidelines for the characterization of postnatal CNVs, and these recommendations should be utilized (Genet Med (2011)13: 680-685). Exceptions to these interpretive correlations will occur, and clinical judgment should always be exercised.