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
12833159 Mburu et al. 2003 identified a consanguineous family from Jordan with 5 autosomal recessive segregations with profound prelingual deafness (6 affected, 11 unaffected). The variant was NM_015404.3:c.2332C>T (p.Arg778Ter) which causes a stop codon in exon 10/12 and therefore leads to absent or truncated protein.
15841483 Tilili et al. 2005 identified a consanguineous family with profound prelingual deafness. The NM_015404.3:c.2423delG (p.Gly808fsX12) variant segregated with disease 3 times. Of note, this variant occurs in the second to last exon (11/12) though the stop codon that it produces does occur more than 50 bp from the final intron. It is unclear as to whether the product of this transcript will undergo nonsense mediated decay. However, this variant still provides support for this gene being associated with autosomal recessive prelingual profound deafness.

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.