NM_001371623.1(TCOF1):c.4372_4376del (p.Lys1458fs) AND Treacher Collins syndrome 1

Germline classification:: Pathogenic (7 submissions)
Last evaluated:: Dec 3, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000004169.20

Allele description [Variation Report for NM_001371623.1(TCOF1):c.4372_4376del (p.Lys1458fs)]

NM_001371623.1(TCOF1):c.4372_4376del (p.Lys1458fs)

Gene:

TCOF1:treacle ribosome biogenesis factor 1 [Gene - OMIM - HGNC]

Variant type:

Microsatellite

Cytogenetic location:

5q32

Genomic location:

Preferred name:

NM_001371623.1(TCOF1):c.4372_4376del (p.Lys1458fs)

HGVS:

NC_000005.10:g.150398375AAGAA[1]
NG_011341.1:g.45737AAGAA[1]
NM_000356.4:c.4138_4142del
NM_001135243.2:c.4369_4373del
NM_001135244.2:c.4258_4262del
NM_001135245.2:c.4141_4145del
NM_001195141.2:c.4255_4259del
NM_001371623.1:c.4372_4376delMANE SELECT
NP_000347.2:p.Lys1380fs
NP_001128715.1:p.Lys1457fs
NP_001128716.1:p.Lys1420fs
NP_001128717.1:p.Lys1381fs
NP_001182070.1:p.Lys1419fs
NP_001358552.1:p.Lys1458fs
NC_000005.9:g.149777936_149777940del
NC_000005.9:g.149777938AAGAA[1]
NM_000356.3:c.4138_4142del
NM_001135243.1:c.4369_4373delAAGAA
NM_001371623.1:c.4372_4376del

Protein change:

K1380fs

Links:

OMIM: 606847.0004; dbSNP: rs587776582

NCBI 1000 Genomes Browser:

rs587776582

Molecular consequence:

NM_000356.4:c.4138_4142del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001135243.2:c.4369_4373del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001135244.2:c.4258_4262del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001135245.2:c.4141_4145del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001195141.2:c.4255_4259del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001371623.1:c.4372_4376del - frameshift variant - [Sequence Ontology: SO:0001589]

Observations:

Condition(s)

Name:: Treacher Collins syndrome 1 (TCS1)
Identifiers:: MONDO: MONDO:0007944; MedGen: CN315775; Orphanet: 861; OMIM: 154500

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000024335	OMIM	no assertion criteria provided	Pathogenic (Oct 1, 2000)	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 11013442, 9042910
SCV000597428	Genetic Services Laboratory, University of Chicago	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 16, 2017)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000776781	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 3, 2023)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 8894686, 9042910, 11013442, 20003452, 21951868, 22317976, 28492532
SCV000996042	Johns Hopkins Genomics, Johns Hopkins University	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 31, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001438081	Autoinflammatory diseases unit, CHU de Montpellier	no assertion criteria provided	Pathogenic (Apr 14, 2016)	de novo	clinical testing
SCV002552096	Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand	no assertion criteria provided	Pathogenic	unknown	research
SCV002572879	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Sep 1, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 9042910, 25741868

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	1	not provided	not provided	1	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	de novo	yes	2	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	unknown	yes	1	not provided	not provided	1	not provided	research

Citations

PubMed

Treacher Collins syndrome may result from insertions, deletions or splicing mutations, which introduce a termination codon into the gene.

Gladwin AJ, Dixon J, Loftus SK, Edwards S, Wasmuth JJ, Hennekam RC, Dixon MJ.

Hum Mol Genet. 1996 Oct;5(10):1533-8.

PubMed [citation]

PMID:: 8894686

High mutation detection rate in TCOF1 among Treacher Collins syndrome patients reveals clustering of mutations and 16 novel pathogenic changes.

Splendore A, Silva EO, Alonso LG, Richieri-Costa A, Alonso N, Rosa A, Carakushanky G, Cavalcanti DP, Brunoni D, Passos-Bueno MR.

Hum Mutat. 2000 Oct;16(4):315-22. Review.

PubMed [citation]

PMID:: 11013442

See all PubMed Citations (8)

Details of each submission

From OMIM, SCV000024335.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (2)

Description

In a review of mutations in the TCOF1 gene causing Treacher Collins syndrome (TCS1; 154500), Splendore et al. (2000) found that the most frequent recurring mutation was a 5-bp deletion in exon 24 (4135-4139delGAAAA). This mutation was reported in 7 families by Edwards et al. (1997), was found by Splendore et al. (2000) in 6 unrelated patients, and was said to be responsible for approximately 16% of all reported cases.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Genetic Services Laboratory, University of Chicago, SCV000597428.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Invitae, SCV000776781.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

This sequence change creates a premature translational stop signal (p.Lys1457Glufs*12) in the TCOF1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TCOF1 are known to be pathogenic (PMID: 8894686, 22317976). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with Treacher Collins syndrome (PMID: 9042910, 11013442, 20003452, 21951868, 22317976). ClinVar contains an entry for this variant (Variation ID: 3963). For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Johns Hopkins Genomics, Johns Hopkins University, SCV000996042.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Autoinflammatory diseases unit, CHU de Montpellier, SCV001438081.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	de novo	yes	not provided	not provided	not provided		2	not provided	not provided	not provided

From Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand, SCV002552096.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	research	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	1	not provided	not provided		1	not provided	not provided	not provided

From 3billion, SCV002572879.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (2)

Description

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). 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 at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000003963 / PMID: 9042910). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided

Last Updated: May 12, 2024

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