VCV000543946.8 - ClinVar

NC_000005.10:g.(?_150387882)_(150399068_?)del

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

NC_000005.10:g.(?_150387882)_(150399068_?)del

Variation ID: 543946 Accession: VCV000543946.8

Type and length

Deletion, 11,187 bp

Location

Cytogenetic: 5q32 5: 150387882-150399068 (GRCh38) [ NCBI UCSC ] 5: 149767445-149778631 (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	May 28, 2018	Jun 9, 2024	Dec 27, 2017

HGVS

Nucleotide	Protein	Molecular consequence
NC_000005.10:g.(?_150387882)_(150399068_?)del
NC_000005.9:g.(?_149767445)_(149778631_?)del

Protein change

Other names

Canonical SPDI

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.
TCOF1		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	841	880
LOC129994988	-	-	-	GRCh38	-	9
LOC129994989	-	-	-	GRCh38	-	15

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.
Treacher Collins syndrome 1	Pathogenic (1)	criteria provided, single submitter	Dec 27, 2017	RCV000654887.9

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 (Dec 27, 2017)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Treacher Collins syndrome 1 Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000776791.5 First in ClinVar: May 28, 2018 Last updated: Jun 09, 2024	Publications: PubMed (2) PubMed: 9811939‚ 9736782 Comment: For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that the final 160-190 amino acids of the TCOF1 protein contain … (more) For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that the final 160-190 amino acids of the TCOF1 protein contain nuclear and nucleolar localization signals. Deletion of these residues leads to mislocalization of the protein in cell culture-based assays (PMID: 9811939, 9736782). This variant is a gross deletion of the genomic region encompassing exons 18-26 of the TCOF1 gene. The 5' boundary is likely confined to intron 17. The 3' end of this event is unknown as it extends through the termination codon beyond the assayed region for this gene and may encompass additional genes. While this deletion is not anticipated to result in nonsense mediated decay, it is expected to create a truncated protein product or disrupt mRNA translation. Gross deletion of TCOF1 exons 18-26 has been reported in an individual affected with Treacher Collins syndrome (Invitae). (less)

Comment:

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that the final 160-190 amino acids of the TCOF1 protein contain nuclear and nucleolar localization signals. Deletion of these residues leads to mislocalization of the protein in cell culture-based assays (PMID: 9811939, 9736782). This variant is a gross deletion of the genomic region encompassing exons 18-26 of the TCOF1 gene. The 5' boundary is likely confined to intron 17. The 3' end of this event is unknown as it extends through the termination codon beyond the assayed region for this gene and may encompass additional genes. While this deletion is not anticipated to result in nonsense mediated decay, it is expected to create a truncated protein product or disrupt mRNA translation. Gross deletion of TCOF1 exons 18-26 has been reported in an individual affected with Treacher Collins syndrome (Invitae).

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
The Treacher Collins syndrome (TCOF1) gene product, treacle, is targeted to the nucleolus by signals in its C-terminus.	Winokur ST	Human molecular genetics	1998	PMID: 9811939
Mutations in the Treacher Collins syndrome gene lead to mislocalization of the nucleolar protein treacle.	Marsh KL	Human molecular genetics	1998	PMID: 9736782

Text-mined citations for this variant ...

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NC_000005.10:g.(?_150387882)_(150399068_?)del

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...