In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31487502, 28771251, 28562391, 28687524, 35165208, 35032046, 33936649, 26769062)
ClinVar Genomic variation as it relates to human health
NM_024665.7(TBL1XR1):c.1337A>G (p.Tyr446Cys)
Germline
Classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(5)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic
5
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_024665.7(TBL1XR1):c.1337A>G (p.Tyr446Cys)
Variation ID: 225874 Accession: VCV000225874.10
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 3q26.32 3: 177033050 (GRCh38) [ NCBI UCSC ] 3: 176750838 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Nov 13, 2017 Sep 29, 2024 Jun 13, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_024665.7:c.1337A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_078941.2:p.Tyr446Cys missense NM_001321193.3:c.1337A>G NP_001308122.1:p.Tyr446Cys missense NM_001321194.3:c.1337A>G NP_001308123.1:p.Tyr446Cys missense NM_001321195.3:c.1076A>G NP_001308124.1:p.Tyr359Cys missense NM_001374327.1:c.1337A>G NP_001361256.1:p.Tyr446Cys missense NM_001374328.1:c.1337A>G NP_001361257.1:p.Tyr446Cys missense NM_001374329.1:c.1337A>G NP_001361258.1:p.Tyr446Cys missense NM_001374330.1:c.1076A>G NP_001361259.1:p.Tyr359Cys missense NC_000003.12:g.177033050T>C NC_000003.11:g.176750838T>C NG_047195.1:g.169211A>G Q9BZK7:p.Tyr446Cys - Protein change
- Y446C, Y359C
- Other names
- -
- Canonical SPDI
- NC_000003.12:177033049:T:C
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
- -
- Links
- Comment on variant
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| TBL1XR1 | Sufficient evidence for dosage pathogenicity | Little evidence for dosage pathogenicity |
GRCh38 GRCh37 |
422 | 604 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Mar 29, 2023 | RCV000211104.7 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jun 13, 2024 | RCV001589108.6 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
Jul 25, 2023 | RCV003317156.1 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Oct 23, 2018)
|
criteria provided, single submitter
Method: research
|
Pierpont syndrome
Affected status: yes
Allele origin:
unknown
|
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology
Study: AGHI-WGS-HudsonAlpha
Accession: SCV000886433.1 First in ClinVar: Nov 13, 2017 Last updated: Nov 13, 2017 |
Number of individuals with the variant: 1
Clinical Features:
Dislocated radial head (present) , Relative macrocephaly (present) , Abnormal morphology of ulna (present) , Abnormality of femur morphology (present)
|
|
|
Pathogenic
(Jun 13, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV001823387.2
First in ClinVar: Sep 08, 2021 Last updated: Sep 29, 2024 |
Comment:
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); … (more)
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31487502, 28771251, 28562391, 28687524, 35165208, 35032046, 33936649, 26769062) (less)
|
|
|
Pathogenic
(Mar 29, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Pierpont syndrome
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV004293535.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, … (more)
For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TBL1XR1 protein function. ClinVar contains an entry for this variant (Variation ID: 225874). This missense change has been observed in individual(s) with Pierpont syndrome (PMID: 26769062). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 446 of the TBL1XR1 protein (p.Tyr446Cys). (less)
|
|
|
Pathogenic
(Jul 19, 2022)
|
no assertion criteria provided
Method: literature only
|
PIERPONT SYNDROME
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000268061.5
First in ClinVar: May 14, 2016 Last updated: Jul 22, 2022 |
Comment on evidence:
In 6 unrelated patients with Pierpont syndrome (PRPTS; 602342), including the patients originally reported by Pierpont et al. (1998), Heinen et al. (2016) identified a … (more)
In 6 unrelated patients with Pierpont syndrome (PRPTS; 602342), including the patients originally reported by Pierpont et al. (1998), Heinen et al. (2016) identified a de novo heterozygous c.1337A-G transition in the TBL1XR1 gene, resulting in a tyr446-to-cys (Y446C) substitution at a conserved residue in the WD40 domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the dbSNP, 1000 Genomes Project, or Exome Sequencing Project databases. The mutant protein assembled correctly into its complex, but further functional studies were not performed. In a male child with Pierpont syndrome, Kahlert et al. (2017) identified heterozygosity for the Y446C mutation in the TBL1XR1 gene. The mutation was confirmed by Sanger sequencing. By whole-exome sequencing in a boy with Pierpont syndrome, Tesarova et al. (2022) identified heterozygosity for the Y446C mutation in the TBL1XR1 gene. The mutation, which occurred de novo, was confirmed by Sanger sequencing. (less)
|
|
|
Likely pathogenic
(Jul 25, 2023)
|
no assertion criteria provided
Method: clinical testing
|
Malignant lymphoma, large B-cell, diffuse
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
Wasik Lab, Fox Chase Cancer Center
Accession: SCV004020298.1
First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023 |
Comment:
This variant was observed in a patient with DLBCL that presented in leukemic form, best classified as MCD/C5 DLBCL, an ABC subtype. Despite an initial … (more)
This variant was observed in a patient with DLBCL that presented in leukemic form, best classified as MCD/C5 DLBCL, an ABC subtype. Despite an initial good clinical response to BTK inhibitor ibrutinib, anti-CD20 antibody rituxan, alkylating agent bendamustine, and hematopoietic stem-cell transplant, the lymphoma relapsed, accompanied by morphologic and molecular evidence of disease progression. TBL1XR1 K398* and Y446C were detected in the tumor at presentation and after recurrence, with the K398* allele frequency doubling from 30% to 60%. These TBL1XR1 alterations result in the loss of interaction of the SMRT/NCOR1 complex with the germinal center transcriptional repressor BCL-6. Instead, BCL-6 binding to the transcription factor BACH2 complex is induced. This binding realignment blocks germinal-center B cells from developing into plasma cells by repressing PRDM1, a transcriptional repressor. Additionally, at relapse, this tumor had arm-level loss of 6q which contains PRDM1 (Figure 2). Inactivation of PRDM1 is critical to pathogenesis of ABC-DLBCL (Pasqualucci et al. 2006; Calado et al. 2010; Mandelbaum et al. 2010). Collectively, TBL1XR1 mutations and loss of PRDM1 prevent B-cell differentiation towards plasma cells and drive them toward the memory B-cell program (Venturutti and Melnick 2020; Venturutti et al. 2020), most likely contributing to malignant cell transformation. (less)
Indication for testing: DLBCL
Age: 50-59 years
Sex: female
Comment on evidence:
Peripheral blood containing DLBCL collected for sequencing at initial diagnosis August 2018. Tumor tissue sequenced at recurrence September 2019.
Testing laboratory: Genoptix
Date variant was reported to submitter: 2019-10-10
Testing laboratory interpretation: Pathogenic
|
Comment:
Comment:
For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TBL1XR1 protein function. ClinVar contains an entry for this variant (Variation ID: 225874). This missense change has been observed in individual(s) with Pierpont syndrome (PMID: 26769062). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 446 of the TBL1XR1 protein (p.Tyr446Cys).
Comment:
This variant was observed in a patient with DLBCL that presented in leukemic form, best classified as MCD/C5 DLBCL, an ABC subtype. Despite an initial good clinical response to BTK inhibitor ibrutinib, anti-CD20 antibody rituxan, alkylating agent bendamustine, and hematopoietic stem-cell transplant, the lymphoma relapsed, accompanied by morphologic and molecular evidence of disease progression. TBL1XR1 K398* and Y446C were detected in the tumor at presentation and after recurrence, with the K398* allele frequency doubling from 30% to 60%. These TBL1XR1 alterations result in the loss of interaction of the SMRT/NCOR1 complex with the germinal center transcriptional repressor BCL-6. Instead, BCL-6 binding to the transcription factor BACH2 complex is induced. This binding realignment blocks germinal-center B cells from developing into plasma cells by repressing PRDM1, a transcriptional repressor. Additionally, at relapse, this tumor had arm-level loss of 6q which contains PRDM1 (Figure 2). Inactivation of PRDM1 is critical to pathogenesis of ABC-DLBCL (Pasqualucci et al. 2006; Calado et al. 2010; Mandelbaum et al. 2010). Collectively, TBL1XR1 mutations and loss of PRDM1 prevent B-cell differentiation towards plasma cells and drive them toward the memory B-cell program (Venturutti and Melnick 2020; Venturutti et al. 2020), most likely contributing to malignant cell transformation.
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31487502, 28771251, 28562391, 28687524, 35165208, 35032046, 33936649, 26769062)
Comment:
For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TBL1XR1 protein function. ClinVar contains an entry for this variant (Variation ID: 225874). This missense change has been observed in individual(s) with Pierpont syndrome (PMID: 26769062). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 446 of the TBL1XR1 protein (p.Tyr446Cys).
Comment:
This variant was observed in a patient with DLBCL that presented in leukemic form, best classified as MCD/C5 DLBCL, an ABC subtype. Despite an initial good clinical response to BTK inhibitor ibrutinib, anti-CD20 antibody rituxan, alkylating agent bendamustine, and hematopoietic stem-cell transplant, the lymphoma relapsed, accompanied by morphologic and molecular evidence of disease progression. TBL1XR1 K398* and Y446C were detected in the tumor at presentation and after recurrence, with the K398* allele frequency doubling from 30% to 60%. These TBL1XR1 alterations result in the loss of interaction of the SMRT/NCOR1 complex with the germinal center transcriptional repressor BCL-6. Instead, BCL-6 binding to the transcription factor BACH2 complex is induced. This binding realignment blocks germinal-center B cells from developing into plasma cells by repressing PRDM1, a transcriptional repressor. Additionally, at relapse, this tumor had arm-level loss of 6q which contains PRDM1 (Figure 2). Inactivation of PRDM1 is critical to pathogenesis of ABC-DLBCL (Pasqualucci et al. 2006; Calado et al. 2010; Mandelbaum et al. 2010). Collectively, TBL1XR1 mutations and loss of PRDM1 prevent B-cell differentiation towards plasma cells and drive them toward the memory B-cell program (Venturutti and Melnick 2020; Venturutti et al. 2020), most likely contributing to malignant cell transformation.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Pierpont syndrome due to mutation c.1337A>G in TBL1XR1 gene. | Tesarova M | Clinical dysmorphology | 2022 | PMID: 35165208 |
| The dangers of déjà vu: memory B cells as the cells of origin of ABC-DLBCLs. | Venturutti L | Blood | 2020 | PMID: 32932517 |
| TBL1XR1 Mutations Drive Extranodal Lymphoma by Inducing a Pro-tumorigenic Memory Fate. | Venturutti L | Cell | 2020 | PMID: 32619424 |
| Pierpont syndrome: report of a new patient. | Kahlert AK | Clinical dysmorphology | 2017 | PMID: 28562391 |
| A specific mutation in TBL1XR1 causes Pierpont syndrome. | Heinen CA | Journal of medical genetics | 2016 | PMID: 26769062 |
| Constitutive canonical NF-κB activation cooperates with disruption of BLIMP1 in the pathogenesis of activated B cell-like diffuse large cell lymphoma. | Calado DP | Cancer cell | 2010 | PMID: 21156282 |
| BLIMP1 is a tumor suppressor gene frequently disrupted in activated B cell-like diffuse large B cell lymphoma. | Mandelbaum J | Cancer cell | 2010 | PMID: 21156281 |
| Inactivation of the PRDM1/BLIMP1 gene in diffuse large B cell lymphoma. | Pasqualucci L | The Journal of experimental medicine | 2006 | PMID: 16492805 |
| Plantar lipomatosis, unusual facial phenotype and developmental delay: a new MCA/MR syndrome. | Pierpont ME | American journal of medical genetics | 1998 | PMID: 9450851 |
Text-mined citations for rs878854402 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Oct 08, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.
Please note the erratum published in http://jmg.bmj.com/content/53/6/430.full clarifies the alternate allele to be G, not C