ClinVar Genomic variation as it relates to human health

The heterozygous p.Gln1196ProfsTer14 variant in ARID1B was identified by our study in 1 individual with Coffin-Siris syndrome 1. Trio exome analysis showed this variant to be de novo. This variant is assumed de novo in another individual, but maternity and paternity have not been confirmed (PMID: 23906836). The variant was absent from large population studies, and has been reported in ClinVar (Variation ID: 694703) as pathogenic by Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 1196 and leads to a premature termination codon 14 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of function of ARID1B is an established disease mechanism in Coffin-Siris syndrome 1. In summary, this variant meets criteria to be classified as pathogenic for Coffin-Siris syndrome 1 in an autosomal dominant manner based on the predicted impact of the variant, its absence from control populations, and its de novo status. ACMG/AMP Criteria applied: PVS1, PS2, PM2 (Richards 2015).

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Coffin-Siris syndrome (MIM#135900). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0701 - Other NMD predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been observed in at least five unrelated individuals with Coffin-Siris syndrome (MIM#135900), including two de novo reports (ClinVar, PMIDs: 31164752, 23906836). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23906836, 23160955, 25249037, 28191890, 31332282, 31981491, 25363768, 30349098, 31526516, 31785789)

The c.3586dupC pathogenic mutation, located in coding exon 14 of the ARID1B gene, results from a duplication of C at nucleotide position 3586, causing a translational frameshift with a predicted alternate stop codon (p.Q1196Pfs*14). This alteration has been detected as de novo occurrences in individuals with Nicolaides–Baraitser syndrome or Coffin–Siris syndrome (Wieczorek D et al. Hum. Mol. Genet., 2013 Dec;22:5121-35; Mari F et al. Brain Dev., 2015 May;37:527-36) as well as in individuals with autism spectrum disorder (O'Roak BJ et al. Science, 2012 Dec;338:1619-22). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.