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
11845407 Brouillard et al. (2002) identified an intragenic deletion and 13 sequence-level mutations (predicted to result in a loss-of-function) in the GLMN gene in 14 unrelated families with autosomal dominant glomuvenous malformations (GVMs), including an 8.4 kb intragenic deletion removing exons 8-13 and two nonsense mutations. Acquisition of a somatic ?second hit? GLMN mutation was demonstrated for one individual in this cohort, supporting a 2-hit mode of inheritance for GVMs. The authors also report that, amongst the families studied, observed penetrance of the mutations was 88.6% and rose to 92.7% at age 20 years.
15689436 Brouillard et al. (2005) reported 3 novel frameshift mutations and identify 23 additional families with GLMN mutations and GVM.
22092580 Borroni et al. (2011) describe a novel frameshift mutation (p.Leu374LeufsX4 ) segregating with the phenotype in a family with multiple GVMs. The mutation was absent in 190 controls.

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.