2-161423752-CGCTGCAG-CGCTGCAGGCTGCAG

Variant names:

• chr2-161423752-C-CGCTGCAG
• rs869312704
• NM_006593.4:c.1588_1594dupGGCTGCA

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_006593.4(TBR1):​c.1588_1594dupGGCTGCA​(p.Thr532ArgfsTer144) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TBR1 NM_006593.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:20 O:1
• Conservation: PhyloP100: -1.77

Genes affected

TBR1 (HGNC:11590): (T-box brain transcription factor 1) This gene is a member of a conserved family of genes that share a common DNA-binding domain, the T-box. T-box genes encode transcription factors involved in the regulation of numerous developmental processes. In mouse, the ortholog of this gene is expressed in the cerebral cortex, hippocampus, amygdala and olfactory bulb and is thought to play an important role in neuronal migration and axonal projection. In mouse, the C-terminal region of this protein was found to be necessary and sufficient for association with the guanylate kinase domain of calcium/calmodulin-dependent serine protein kinase. [provided by RefSeq, Dec 2015]

ENSG00000224076 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.222 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-161423752-C-CGCTGCAG is Pathogenic according to our data. Variant chr2-161423752-C-CGCTGCAG is described in ClinVar as [Likely_pathogenic]. Clinvar id is 224144.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBR1	NM_006593.4	c.1588_1594dupGGCTGCA	p.Thr532ArgfsTer144	frameshift_variant	Exon 6 of 6	ENST00000389554.8	NP_006584.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBR1	ENST00000389554.8	c.1588_1594dupGGCTGCA	p.Thr532ArgfsTer144	frameshift_variant	Exon 6 of 6	1	NM_006593.4	ENSP00000374205.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 38

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:20 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autism, susceptibility to, 5 Pathogenic:7

Jun 22, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: TBR1 c.1588_1594dupGGCTGCA (p.Thr532ArgfsX144) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 104902 control chromosomes (gnomAD). c.1588_1594dupGGCTGCA has been reported in the literature as a de-novo occurrence in multiple individuals affected with intellectual disability (e.g. Gilissen_2014, Thevenon_2016, Bowling_2017, Vegas_2018, Bruel_2019). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Twelve ClinVar submissions (evaluation after 2014) cite the variant as pathogenic (n=3) and likely pathogenic (n=9), including eight reports of the variant as de-novo in origin. Based on the evidence outlined above, the variant was classified as pathogenic. -

Jun 01, 2022

Solve-RD Consortium

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: provider interpretation

Variant confirmed as disease-causing by referring clinical team -

-

Developmental and Behavioral Pediatrics, First Affiliated Hospital of Jilin University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 11, 2023

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: Frameshift: predicted to result in a loss or disruption of normal protein function through protein truncation. Multiple pathogenic variants are reported in the predicted truncated region. The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 28554332, 30268909, 31231135). The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000224144 /3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Jun 07, 2019

Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 03, 2022

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG classification criteria: PVS1 strong, PS4 moderated, PM2 moderated, PM6 strong -

Dec 19, 2018

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:3

Oct 10, 2015

HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Jul 07, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Frameshift variant predicted to result in protein truncation, as the last 151 amino acids are replaced with 143 different amino acids, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (HGMD); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 24896178, 30268909, 26757139, 28554332, 31231135, 32959227) -

Dec 01, 2017

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Intellectual developmental disorder with speech delay, autism, and dysmorphic facies Pathogenic:1

Jan 25, 2023

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

The p.Thr532ArgfsTer144 variant in TBR1 was identified by our study in one individual with global developmental delay and polymicrogyria. Trio exome analysis showed this variant to be de novo. The p.Thr532ArgfsTer144 variant in TBR1 has been previously reported in the literature in 7 unrelated individuals with intellectual developmental disorder with autism and speech delay (PMID: 32959227, PMID: 31231135, PMID: 26757139, PMID: 24896178, PMID: 30268909, PMID: 28554332). The number of reported affected individuals with this variant is greater than expected compared to non-affected individuals with this variant. This variant was found to be de novo in at least 7 individuals with confirmed paternity and maternity (PMID: 32959227, PMID: 30268909, PMID: 24896178, PMID: 26757139, PMID: 28554332, PMID: 31231135, SCV000599285.1, SCV000747915.2, SCV000747914.2, SCV001371835.1, SCV001371828.1, SCV000747913.2, SCV001149955.1, SCV000965704.1). This variant has also been reported in ClinVar (Variation ID: 224144) and has been interpreted as pathogenic or likely pathogenic by multiple submitters. This variant was absent from large population studies. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 532 and leads to a premature termination codon 144 amino acids downstream. This termination codon occurs within the terminal 50 bases of the last exon and is more likely to escape nonsense mediated decay (NMD) and result in a truncated protein. Heterozygous loss of function of the TBR1 gene is strongly associated to autosomal dominant intellectual developmental disorder with autism and speech delay. In summary, this variant meets criteria to be classified as pathogenic for intellectual developmental disorder with autism and speech delay. ACMG/AMP Criteria applied: PVS1_Supporting, PM2_Supporting, PS2_VeryStrong, PS4 (Richards 2015). -

Inborn genetic diseases Pathogenic:1

Jun 05, 2018

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Severe global developmental delay Pathogenic:1

Oct 30, 2017

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autistic behavior;C1837397:Severe global developmental delay;C4022749:Abnormal brainstem MRI signal intensity;C4023681:Delayed fine motor development Pathogenic:1

Jan 12, 2019

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autistic behavior;C2237142:Moderate global developmental delay Pathogenic:1

Mar 16, 2017

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Neurodevelopmental disorder Pathogenic:1

Feb 09, 2016

Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Seizure;C0751837:Gait ataxia;C1837397:Severe global developmental delay;C2938983:Focal cortical dysplasia;C4023681:Delayed fine motor development Pathogenic:1

Oct 15, 2018

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autistic behavior Pathogenic:1

Jan 01, 2014

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Gait ataxia;C1837397:Severe global developmental delay;C1849172:Hypoplasia of the frontal lobes;C4023681:Delayed fine motor development Pathogenic:1

Feb 02, 2018

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autistic behavior;C1837397:Severe global developmental delay Pathogenic:1

Sep 01, 2014

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Intellectual disability Other:1

-

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs869312704; hg19: chr2-162280263;