rs869320802

chr4-1213028-G-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PP3_Moderate PP5_Very_Strong

The NM_001012614.2(CTBP1):c.991C>T(p.Arg331Trp) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CTBP1 NM_001012614.2 missense, splice_region
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 7.26

Genes affected

CTBP1 (HGNC:2494): (C-terminal binding protein 1) This gene encodes a protein that binds to the C-terminus of adenovirus E1A proteins. This phosphoprotein is a transcriptional repressor and may play a role during cellular proliferation. This protein and the product of a second closely related gene, CTBP2, can dimerize. Both proteins can also interact with a polycomb group protein complex which participates in regulation of gene expression during development. Alternative splicing of transcripts from this gene results in multiple transcript variants. [provided by RefSeq, Jul 2008]

CTBP1-AS (HGNC:48337): (CTBP1 antisense RNA)

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.888
• PP5: Variant 4-1213028-G-A is Pathogenic according to our data. Variant chr4-1213028-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 225758.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-1213028-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CTBP1	NM_001012614.2	c.991C>T	p.Arg331Trp	missense_variant, splice_region_variant	9/10	ENST00000382952.8
CTBP1-AS	NR_104331.1	n.1108+258G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CTBP1	ENST00000382952.8	c.991C>T	p.Arg331Trp	missense_variant, splice_region_variant	9/10	1	NM_001012614.2	A1
CTBP1-AS	ENST00000625256.1	n.1108+258G>A		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypotonia, ataxia, developmental delay, and tooth enamel defect syndrome Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg	Apr 23, 2024	This variant has been identified by standard clinical testing. Selected ACMG criteria: Pathogenic (II):PP3;PP2;PM2;PS3;PS2 -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 08, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Oct 27, 2020	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. -
Pathogenic, criteria provided, single submitter	clinical testing	New York Genome Center	Aug 06, 2021	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. -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Jan 03, 2022	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. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 28, 2018	- -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 23, 2023	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) -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Apr 18, 2020	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. -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 27, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
Cadd	Pathogenic	32
Dann	Pathogenic	1.0
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Pathogenic	0.63	D
MetaRNN	Pathogenic	0.89	D;D
MetaSVM	Uncertain	0.55	D
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-6.9	D;D
REVEL	Pathogenic	0.74
Sift	Uncertain	0.0060	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	.;D
Vest4		0.69
MutPred		0.52		.;Loss of helix (P = 0.0376);
MVP		0.76
MPC		2.2
ClinPred		1.0	D
GERP RS		2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.72
gMVP		0.87

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs869320802; hg19: chr4-1206816;