ClinGen Dosage Sensitivity Curation Page

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  • Curation Status: Complete

Location Information

Select assembly: (NC_000006.11) (NC_000006.12)
Evidence for haploinsufficiency phenotype
PubMed ID Description
22542183 Iossifov et al. (2012) performed whole exome sequencing on a subset of 343 families from the Simons Simplex Collection in which there is one child on the autism spectrum and one (or more) normal siblings. They report a single de novo frameshift variant in a male that had been diagnosed with autism.
25284784 Dong et al. (2014) combined a family-based local realignment approach with empirically derived quality metric thresholds to look for de novo indels amongst a sample of previously analyzed whole exome sequencing data from 787 Simons Simplex Collection families. This group confirmed the de novo frameshift variant in RIMS1 first identified in Iossifov et al. (2012) (see PMID 1), and identified another de novo frameshift variant in a different male diagnosed with autism.
27824329 Wang et al. (2016) used single-molecule molecular inversion probes (smMIPs) to sequence the coding regions of 189 autism risk genes in a cohort of 1543 autism probands (1045 from trios) from the Autism Clinical and Genetics Resources in China (ACGC) group. They detected one de novo nonsense variant in an individual diagnosed with autism. In addition, the authors identified 2 inherited frameshift variants, 2 inherited nonsense variants, an inherited missense variant, and an additional frameshift variant of unknown inheritance in RIMS1.

Haploinsufficiency phenotype comments:

Of note, Krumm et al. 2015 (PMID: 25961944) evaluated whole exome sequencing results of 2377 Simons Simplex families (in which a single proband is affected with autism) to determine the effects of private or rare inherited single nucleotide variants (SNVs) and copy number variants (CNVs). They report that private truncating SNVs and rare, inherited CNVs are statistically independent autism risk factors, with odds ratios of 1.11 (p=0.0002) and 1.23 (p=0.01), respectively. The authors identified two private and 6 rare likely gene disrupting (LGD) inherited SNVs in RIMS1 in probands, compared to 3 rare LGD SNVs in RIMS1 in unaffected siblings. They propose that inherited variants may create a sensitized background but are unlikely to be completely penetrant. Additionally, a missense variant in RIMS1 (p. Arg844His) was found to segregate with autosomal dominant cone-rod dystrophy (CORD) within a single 4-generation, non-consanguinous British family. The variant was identified through a candidate gene sequencing approach within a 7 cM region of chromosome 6q14, flanked by the markers D6S430 and D6S1625 (PMIDs: 15665353, 12659814). The authors have written several articles about this family, including one that suggests that those with the variant in the family have "enhanced cognitive function" (PMID: 17237123). This variant is present in ExAC (2 heterozygous individuals from the European non-Finnish cohort) for a population-specifc allele frequency of 0.0001539, and a total allele frequency of 7.177e-05. The database notes that this particular site is covered in fewer than 80% of the individuals in ExAC, which may indicate a low-quality site. Finally, as of January 2018, this gene appears to be somewhat tolerant of loss of function variants (pLI score = 0.03) given the number of observed loss of function variants in the ExAC dataset. While there have been 3 de novo putative loss of function variants in this gene observed in individuals with autism, given the presence of loss of function variation in the normal population (question of incomplete penetrance vs. normal population variation), the role of RIMS1 in human disease is not yet completely understood, therefore, the loss of function score is 1.

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity