VCV001705551.2 - ClinVar

NM_001371623.1(TCOF1):c.2112_2116del (p.Glu704fs)

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, single submitter

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001371623.1(TCOF1):c.2112_2116del (p.Glu704fs)

Variation ID: 1705551 Accession: VCV001705551.2

Type and length

Microsatellite, 5 bp

Location

Cytogenetic: 5q32 5: 150376295-150376299 (GRCh38) [ NCBI UCSC ] 5: 149755858-149755862 (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	Sep 17, 2022	Oct 8, 2024	Sep 1, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_001371623.1:c.2112_2116del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001358552.1:p.Glu704fs	frameshift
NM_000356.4:c.1881_1885del	NP_000347.2:p.Glu627fs	frameshift
NM_001008657.3:c.2112_2116del	NP_001008657.1:p.Glu704fs	frameshift
NM_001135243.1:c.2112_2116del5
NM_001135243.2:c.2112_2116del	NP_001128715.1:p.Glu704fs	frameshift
NM_001135244.2:c.2112_2116del	NP_001128716.1:p.Glu704fs	frameshift
NM_001135245.2:c.1881_1885del	NP_001128717.1:p.Glu627fs	frameshift
NM_001195141.2:c.2112_2116del	NP_001182070.1:p.Glu704fs	frameshift
NC_000005.10:g.150376295GAAGA[1]
NC_000005.9:g.149755858GAAGA[1]
NG_011341.1:g.23657GAAGA[1]

... more HGVS ... less HGVS

Protein change

E627fs, E704fs

Other names

Canonical SPDI

NC_000005.10:150376294:GAAGAGAAGA:GAAGA

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

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	Sep 1, 2022	RCV002283865.1
TCOF1-related disorder	Pathogenic (1)	no assertion criteria provided	May 31, 2024	RCV004729137.1

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 (Sep 01, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Treacher Collins syndrome 1 Affected status: yes Allele origin: germline	3billion Accession: SCV002573015.1 First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022	Publications: PubMed (1) PubMed: 9042910 Comment: The variant is not observed in the gnomAD v2.1.1 dataset. Frameshift variant is predicted to result in a loss or disruption of normal protein function … (more) The variant is not observed in the gnomAD v2.1.1 dataset. Frameshift variant is predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported to be associated with TCOF1-related disorder (PMID: 9042910). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. (less) Clinical Features: Micrognathia (present) , Microtia (present) , Cleft palate (present) , Malar flattening (present)
Pathogenic (May 31, 2024)	no assertion criteria provided Method: clinical testing	TCOF1-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV005340610.1 First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024	Comment: The TCOF1 c.2112_2116del5 variant is predicted to result in a frameshift and premature protein termination (p.Glu704Aspfs52). This variant has been reported in an individual with … (more) The TCOF1 c.2112_2116del5 variant is predicted to result in a frameshift and premature protein termination (p.Glu704Aspfs52). This variant has been reported in an individual with Treacher Collins syndrome (nt1879 del(GAGAA) in Edwards et al. 1997. PubMed ID: 9042910). This variant has not been reported in a large population database, indicating this variant is rare. Frameshift variants in TCOF1 are expected to be pathogenic. This variant is interpreted as pathogenic. (less)

Comment:

The variant is not observed in the gnomAD v2.1.1 dataset. Frameshift variant is predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported to be associated with TCOF1-related disorder (PMID: 9042910). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

Comment:

The TCOF1 c.2112_2116del5 variant is predicted to result in a frameshift and premature protein termination (p.Glu704Aspfs*52). This variant has been reported in an individual with Treacher Collins syndrome (nt1879 del(GAGAA) in Edwards et al. 1997. PubMed ID: 9042910). This variant has not been reported in a large population database, indicating this variant is rare. Frameshift variants in TCOF1 are expected to be pathogenic. This variant is interpreted 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
The mutational spectrum in Treacher Collins syndrome reveals a predominance of mutations that create a premature-termination codon.	Edwards SJ	American journal of human genetics	1997	PMID: 9042910

Text-mined citations for this variant ...

Record last updated Oct 08, 2024

ClinVar Genomic variation as it relates to human health

NM_001371623.1(TCOF1):c.2112_2116del (p.Glu704fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...