ClinGen Dosage Sensitivity Curation Page


Curation Status: Complete

Gene Information

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Evidence for Loss Phenotypes

Evidence for loss of function phenotype
PubMed ID Description
26173930 Au et al. (2015) describe two probands with de novo, loss-of-function variants identified through whole exome sequencing (NM_002140.3: c.953+1dup and NM_002140.3: c.257G>A). The probands have developmental delay, a "common facial phenotype, characterized by long palpebral fissures, ptosis, a broad prominent nasal bridge, hypoplastic alae nasi, an open downturned mouth with a cupid?s bow-shaped upper vermilion and full lower lip, ears with underdeveloped and thick helices, and a unique tongue with a prominent median crease." The authors also decribed the probands as having a "connective tissue and skeletal phenotype with features that partially overlap with TGF? pathway-related disorders such as Loeys?Dietz or Shprintzen?Goldberg syndrome." Western blot studies of fibroblasts from Proband 2 (c.257G>A) demonstrated significantly decreased hnRNPK protein compared to controls (48.5%).
26954065 Lange et al. (2016) describe an additional proband with features overlapping those described in Au et al. 2015, including "intellectual disability, distinctive facial dysmorphism and skeletal/connective tissue abnormalities." This individual was also found to have a de novo loss-of-function variant, c.931_932insTT, in HNRNPK by whole exome sequencing.

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.