VCV002041505.2 - ClinVar

NM_016614.3(TDP2):c.400C>T (p.Arg134Ter)

Germline

Classification

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.

(2)

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

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_016614.3(TDP2):c.400C>T (p.Arg134Ter)

Variation ID: 2041505 Accession: VCV002041505.2

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 6p22.3 6: 24658586 (GRCh38) [ NCBI UCSC ] 6: 24658814 (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	Feb 8, 2023	Nov 24, 2024	May 13, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_016614.3:c.400C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_057698.2:p.Arg134Ter	nonsense
NC_000006.12:g.24658586G>A
NC_000006.11:g.24658814G>A
NG_052787.1:g.13302C>T

Protein change

R134*

Other names

p.Arg134*

Canonical SPDI

NC_000006.12:24658585:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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

VarSome

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
Gene	OMIM	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.
TDP2		-	-	GRCh38 GRCh37	42	63

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.
not provided	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	May 13, 2024	RCV002903021.3

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 (Jul 05, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV003248846.1 First in ClinVar: Feb 07, 2023 Last updated: Feb 07, 2023	Publications: PubMed (4) PubMed: 24658003‚ 31410782‚ 32651480‚ 34606976 Comment: This sequence change creates a premature translational stop signal (p.Arg134) in the TDP2 gene. It is expected to result in an absent or disrupted protein … (more) This sequence change creates a premature translational stop signal (p.Arg134) in the TDP2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TDP2 are known to be pathogenic (PMID: 24658003). This variant is present in population databases (no rsID available, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with spinocerebellar ataxia (PMID: 31410782, 32651480, 34606976). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (May 13, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV005413721.1 First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024	Publications: PubMed (6) PubMed: 31410782‚ 32651480‚ 32653827‚ 33921670‚ 34606976‚ 38433132 Comment: PM2, PM3_supporting, PVS1 Number of individuals with the variant: 1

Comment:

This sequence change creates a premature translational stop signal (p.Arg134*) in the TDP2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TDP2 are known to be pathogenic (PMID: 24658003). This variant is present in population databases (no rsID available, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with spinocerebellar ataxia (PMID: 31410782, 32651480, 34606976). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.

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:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
A novel pathogenic variant in TDP2 causes spinocerebellar ataxia autosomal recessive 23 accompanied by pituitary tumor and hyperhidrosis: a case report.	Zheng Y	Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology	2024	PMID: 38433132
A novel non-sense mutation in TDP2 causes spinocerebellar ataxia autosomal recessive 23 accompanied by bilateral upward gaze; report of a case and review of the literature.	Zoghi S	European journal of medical genetics	2021	PMID: 34606976
Next-Generation Sequencing Technologies and Neurogenetic Diseases.	Sun H	Life (Basel, Switzerland)	2021	PMID: 33921670
Untangling trapped topoisomerases with tyrosyl-DNA phosphodiesterases.	Zagnoli-Vieira G	DNA repair	2020	PMID: 32653827
Characterization of a novel loss-of-function variant in TDP2 in two adult patients with spinocerebellar ataxia autosomal recessive 23 (SCAR23).	Errichiello E	Journal of human genetics	2020	PMID: 32651480
Consolidating the Role of TDP2 Mutations in Recessive Spinocerebellar Ataxia Associated with Pediatric Onset Drug Resistant Epilepsy and Intellectual Disability (SCAR23).	Ciaccio C	Cerebellum (London, England)	2019	PMID: 31410782
TDP2 protects transcription from abortive topoisomerase activity and is required for normal neural function.	Gómez-Herreros F	Nature genetics	2014	PMID: 24658003

Text-mined citations for this variant ...

Record last updated Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NM_016614.3(TDP2):c.400C>T (p.Arg134Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...