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
30564305 Guo H et al. 2018. This group sequenced 85 genes in 599 probands and 187 autism candidate genes in an additional 784 probands, and identified likely gene-disrupting (LGD) de novo mutations in 13 genes. In figure 1, three de novo LOF variants (p.M289Vfs*3, p.D643Kfs*3, p.S1287*) as well as a missense variant (p.Y325C) were identified in RALGAPB in four ASD patients separately. p.M289Vfs*3 was reported in an ASC (Autism Sequencing Consortium) patient, p.S1287* was reported in a patient with epilepsy in EPI4K study. p.D643Kfs*3 and p.Y325C were reported ASD patients in this study. The authors state that they did not observe other potential pathogenic mutations in other ASD risk genes sequenced in this study in the patients with RALGAPB de novo mutations.
23934111 Allen AS et. al., 2013 . This group reported a screen for de novo variants in patients with classic epileptic encephalopathies. They sequenced the exomes of 264 trios, and confirmed 329 de novo variants. Among those, a de novo nonsense mutation (g. 37195781C>G) identified in gene RALGAPB in trio # CQ. In trio # CQ, two other de novo missense variants (predicted to be damaging) were also identified, one in NLGN2 and the other one in NLRP5.
25363760 De Rubeis S et. al., 2014. This group conducted ASD WES study, sequenced 3976 ASD subjects (including 2303 trios), and 6059 unrelated controls. In patient #DEASD_0338_001, a de novo frameshift variant (g. 37137843CAT>C) was identified. Meanwhile, a de novo missense variant in LPHN1 was also found in this patient.

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.