ClinVar Genomic variation as it relates to human health

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27094857, 28135719, 28191890, 29878067, 31041561, 32167997, 31618753, 33192249, 28252636, 31785789, 36341169, 34732400)

This variant is not present in population databases (ExAC no frequency). For these reasons, this variant has been classified as Pathogenic. This variant has been reported to affect CTBP1 protein function (PMID: 31041561). This variant has been observed in individual(s) with hypotonia, ataxia, developmental delay, and tooth enamel defect syndrome (PMID: 31041561, 29878067, 28955726, 27094857). In at least one individual the variant was observed to be de novo. This variant is also known as c.991C>T (p.R331W) in the literature. ClinVar contains an entry for this variant (Variation ID: 225758). This sequence change replaces arginine with tryptophan at codon 342 of the CTBP1 protein (p.Arg342Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan.

The CTBP1 c.1024C>T (p.(Arg342Trp) missense variant, also known as c.991C>T p.(Arg331Trp) has been identified in individuals with a phenotype consistent with hypotonia, ataxia, developmental delay, and tooth enamel defect syndrome (Beck et al. 2016; Sommerville et al. 2017; Beck et al. 2019). The c.1024C>T variant occurred de novo in all cases except for one individual, in whom the variant was inherited from their unaffected mother who was found to be low-level mosaic for the variant (Beck et al. 2016; Beck et al. 2019). This variant is not observed in version 2.1.1 of the Genome Aggregation Database. Modeling of the CtBP1-S protein, a short isoform of CtBP1, indicates the location of the p.(Arg331Trp) variant within the alpha-5 region, a C-terminal part of the PXDLS-binding cleft, which is important for recruiting various chromatin-modifying components and interacting with different transcriptional regulators (Beck et al. 2019). Beck et al. (2019) also found that patient fibroblasts carrying the variant were more susceptible to apoptotic cell death, and showed 30-fold higher Noxa protein expression, one of the known CtBP-target apoptotic genes, as compared to 8-fold higher expression in control fibroblasts during glucose deprivation. Based on the available evidence the c.1024C>T (p.(Arg342Trp) variant is classified as pathogenic for hypotonia, ataxia, developmental delay, and tooth enamel defect syndrome.

This variant has been identified by standard clinical testing. Selected ACMG criteria: Pathogenic (II):PP3;PP2;PM2;PS3;PS2

The variant has been previously reported as de novo in a similarly affected individual (PMID: 27094857, PS2_S). It has been observed in at least two similarly affected unrelated individuals (PMID: 27094857, PS4_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.743, PP3_P). A missense variant is a common mechanism associated with Hypotonia (PP2_P). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

The de novo c.991C>T (p.Arg331Trp) missense variant identified in the CTBP1 gene is also known as p.Arg342Trp in the literature. It is a recurrent pathogenic variant that has been reported in at least 12 patients affected with similar phenotypes of global developmental delay, intellectual disability, failure to thrive,hypotonia, ataxia, and tooth enamel defects [PMID: 27094857, 28955726, 31041561]. A subset of patients were noted to have regression of motor and/or languageskills [PMID: 31041561]. At least one of these patients had progressive neurodegenerative disease with evidence of defective mitochondrial dysfunction [PMID:28955726]. The variant is absent from gnomAD(v3) database suggesting it is not a common benign variant in the populations represented in that database. It is reported in the ClinVar database as Pathogenic [Variation ID: 225758]. The p.Arg331Trp variant affects an evolutionarily conserved residue and is predicted deleterious by multiple in silico prediction tools (CADD score = 29, REVEL score = 0.743). The variant is located within the C-terminal region of the PLDLS binding cleft which is thought to interact with chromatin-modifying enzymes and mediates chromatin-dependent gene repression pathways. Functional studies suggest that the p.Arg331Trp variant alters the normal function(s) of the CTBP1 protein [PMID:31041561]. Based on the available evidence, the de novo heterozygous c.991C>T(p.Arg331Trp) missense variant identified in the CTBP1 gene is reported as Pathogenic.

CTBP1: PS2:Very Strong, PM2, PS4:Moderate