VCV002927399.1 - ClinVar

NM_024753.5(TTC21B):c.1479_1482del (p.Thr494fs)

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.

(1)

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, single submitter

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_024753.5(TTC21B):c.1479_1482del (p.Thr494fs)

Variation ID: 2927399 Accession: VCV002927399.1

Type and length

Deletion, 4 bp

Location

Cytogenetic: 2q24.3 2: 165924583-165924586 (GRCh38) [ NCBI UCSC ] 2: 166781093-166781096 (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 29, 2024	Feb 28, 2024	Nov 14, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_024753.5:c.1479_1482del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_079029.3:p.Thr494fs	frameshift
NC_000002.12:g.165924585_165924588del
NC_000002.11:g.166781095_166781098del
NG_030345.1:g.34253_34256del

Protein change

T494fs

Other names

Canonical SPDI

NC_000002.12:165924582:TGTTTG:TG

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.
TTC21B		-	-	GRCh38 GRCh37	1124	1327

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.
Jeune thoracic dystrophy Nephronophthisis	Pathogenic (1)	criteria provided, single submitter	Nov 14, 2023	RCV003781589.2

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 (Nov 14, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Jeune thoracic dystrophy Nephronophthisis Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases. Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV004572175.1 First in ClinVar: Feb 28, 2024 Last updated: Feb 28, 2024	Publications: PubMed (8) PubMed: 18327258‚ 21068128‚ 21258341‚ 23559409‚ 24876116‚ 25492405‚ 27491411‚ 29068549 Comment: This sequence change creates a premature translational stop signal (p.Thr494Serfs3) in the TTC21B gene. It is expected to result in an absent or disrupted protein … (more) This sequence change creates a premature translational stop signal (p.Thr494Serfs3) in the TTC21B gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TTC21B are known to be pathogenic (PMID: 18327258, 21068128, 21258341, 23559409, 24876116, 25492405, 27491411, 29068549). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with TTC21B-related conditions. For these reasons, this variant has been classified as Pathogenic. (less)

Comment:

This sequence change creates a premature translational stop signal (p.Thr494Serfs*3) in the TTC21B gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TTC21B are known to be pathogenic (PMID: 18327258, 21068128, 21258341, 23559409, 24876116, 25492405, 27491411, 29068549). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with TTC21B-related conditions. 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
Expanding the genetic architecture and phenotypic spectrum in the skeletal ciliopathies.	Zhang W	Human mutation	2018	PMID: 29068549
Targeted exome sequencing resolves allelic and the genetic heterogeneity in the genetic diagnosis of nephronophthisis-related ciliopathy.	Kang HG	Experimental & molecular medicine	2016	PMID: 27491411
Whole exome sequencing is an efficient, sensitive and specific method for determining the genetic cause of short-rib thoracic dystrophies.	McInerney-Leo AM	Clinical genetics	2015	PMID: 25492405
A homozygous missense mutation in the ciliary gene TTC21B causes familial FSGS.	Huynh Cong E	Journal of the American Society of Nephrology : JASN	2014	PMID: 24876116
Identification of 99 novel mutations in a worldwide cohort of 1,056 patients with a nephronophthisis-related ciliopathy.	Halbritter J	Human genetics	2013	PMID: 23559409
TTC21B contributes both causal and modifying alleles across the ciliopathy spectrum.	Davis EE	Nature genetics	2011	PMID: 21258341
Mutation analysis of 18 nephronophthisis associated ciliopathy disease genes using a DNA pooling and next generation sequencing strategy.	Otto EA	Journal of medical genetics	2011	PMID: 21068128
THM1 negatively modulates mouse sonic hedgehog signal transduction and affects retrograde intraflagellar transport in cilia.	Tran PV	Nature genetics	2008	PMID: 18327258

Text-mined citations for this variant ...

Record last updated Sep 30, 2024

ClinVar Genomic variation as it relates to human health

NM_024753.5(TTC21B):c.1479_1482del (p.Thr494fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...