ClinVar Genomic variation as it relates to human health
NM_019026.6(TMCO1):c.139_140del (p.Gln46_Ser47insTer)
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_019026.6(TMCO1):c.139_140del (p.Gln46_Ser47insTer)
Variation ID: 420165 Accession: VCV000420165.23
- Type and length
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Microsatellite, 2 bp
- Location
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Cytogenetic: 1q24.1 1: 165768200-165768201 (GRCh38) [ NCBI UCSC ] 1: 165737437-165737438 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Apr 27, 2017 May 1, 2024 Dec 19, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_019026.6:c.139_140del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_061899.3:p.Gln46_Ser47insTer nonsense NM_001256164.1:c.190_191del NP_001243093.1:p.Gln63_Ser64insTer nonsense NM_001256165.1:c.103_104del NP_001243094.1:p.Gln34_Ser35insTer nonsense NM_019026.4:c.292_293delAG NR_045818.1:n.231AG[1] non-coding transcript variant NC_000001.11:g.165768200CT[1] NC_000001.10:g.165737437CT[1] NG_032004.1:g.5720AG[1] - Protein change
- Other names
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- Canonical SPDI
- NC_000001.11:165768199:CTCT:CT
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe 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.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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. |
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TMCO1 | - | - |
GRCh38 GRCh37 |
58 | 79 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Dec 19, 2023 | RCV000481400.6 | |
Pathogenic/Likely pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Feb 9, 2022 | RCV000677638.11 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 26, 2020 | RCV001266610.4 | |
TMCO1-related disorder
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Pathogenic (1) |
criteria provided, single submitter
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Apr 25, 2023 | RCV003419799.4 |
Submissions - Germline
Classification
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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
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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
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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
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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. |
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Pathogenic
(Jul 05, 2017)
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criteria provided, single submitter
Method: clinical testing
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Craniofacial dysmorphism, skeletal anomalies, and impaired intellectual development 1
Affected status: yes
Allele origin:
unknown
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Equipe Genetique des Anomalies du Developpement, Université de Bourgogne
Study: Clinvar_gadteam_Clinical_exome_analysis_3
Accession: SCV000803768.1 First in ClinVar: Aug 25, 2018 Last updated: Aug 25, 2018 |
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Pathogenic
(Oct 22, 2019)
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criteria provided, single submitter
Method: clinical testing
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Craniofacial dysmorphism, skeletal anomalies, and impaired intellectual development 1
Affected status: yes
Allele origin:
germline
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Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV001251436.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
The variant was confirmed as compound heterozygous with a variant of uncertain significance (NM_019026.4: c.197C>T).
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Likely pathogenic
(Jun 19, 2020)
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criteria provided, single submitter
Method: clinical testing
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Craniofacial dysmorphism, skeletal anomalies, and impaired intellectual development 1
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV001653001.1
First in ClinVar: May 29, 2021 Last updated: May 29, 2021 |
Comment:
The c.292_293delAG (p.Ser98X) variant in TMCO1 has been reported (as c.139_140delAG: p.Ser47Ter) in the homozygous state in at least 5 individuals of Amish ancestry and … (more)
The c.292_293delAG (p.Ser98X) variant in TMCO1 has been reported (as c.139_140delAG: p.Ser47Ter) in the homozygous state in at least 5 individuals of Amish ancestry and in 2 additional unrelated individuals with Cerebro-facio-thoracic dysplasia, and segregated with disease in 2 affected members from 1 family (Xin 2010 PMID:20018682, Yates 2018 PMID:30556256). It has also been reported in ClinVar (Variation ID 420165). It has been identified in 0.02 (21/129086) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant creates a premature termination codon at position 98, which is predicted to lead to a truncated or absent protein. Loss of function of the TMCO1 gene is associated with autosomal recessive cerebro-facio-thoracic dysplasia. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive cerebro-facio-thoracic dysplasia. ACMG/AMP Criteria applied: PM2, PVS1_Moderate, PP1, PM3_Strong. (less)
Number of individuals with the variant: 1
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Pathogenic
(Feb 09, 2022)
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criteria provided, single submitter
Method: clinical testing
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Craniofacial dysmorphism, skeletal anomalies, and impaired intellectual development 1
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002809942.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(May 25, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000568828.5
First in ClinVar: Apr 27, 2017 Last updated: Mar 04, 2023 |
Comment:
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This … (more)
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 31028937, 20018682, 31102500, 30556256) (less)
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Pathogenic
(Apr 25, 2023)
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criteria provided, single submitter
Method: clinical testing
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TMCO1-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004118033.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The TMCO1 c.292_293delAG variant is predicted to result in premature protein termination (p.Ser98*). This variant was reported the homozygous state in six individuals from an … (more)
The TMCO1 c.292_293delAG variant is predicted to result in premature protein termination (p.Ser98*). This variant was reported the homozygous state in six individuals from an Old Order Amish family, all with craniofacial dysmorphism, skeletal anomalies, and intellectual disability; the variant was shown to segregate with disease within the family (variant described as c.139_140delAG, p.Ser47Ter in Xin et al. 2010. PubMed ID: 20018682). Further testing of undiagnosed children identified five additional Amish individuals with a similar phenotype, all homozygous for the c.292_293delAG (p.Ser98*) variant (Xin et al. 2010. PubMed ID: 20018682). This variant has also been reported in the homozygous state in three Pakistani brothers and one Scottish individual, all with craniofacial dysmorphism, skeletal anomalies, and intellectual disability (Yates et al. 2019. PubMed ID: 30556256). This variant is reported in 0.016% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-165737436-ACT-A). Other predicted loss-of-function variants in TMCO1 have been reported in affected individuals (Human Gene Mutation Database, https://www.hgmd.cf.ac.uk/). In summary, this variant is interpreted as pathogenic. (less)
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Pathogenic
(Dec 19, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV001591696.3
First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Ser98*) in the TMCO1 gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Ser98*) in the TMCO1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TMCO1 are known to be pathogenic (PMID: 20018682, 23320496, 24194475, 24424126). This variant is present in population databases (rs752176040, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with craniofacial dysmorphism, skeletal anomalies, and mental retardation (PMID: 20018682). It has also been observed to segregate with disease in related individuals. This variant is also known as c.139_140delAG. ClinVar contains an entry for this variant (Variation ID: 420165). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Mar 26, 2020)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV001444786.4
First in ClinVar: Nov 21, 2020 Last updated: May 01, 2024 |
Comment:
The alteration results in a premature stop codon: _x000D_ _x000D_ The c.139_140delAG (p.S47*) alteration, located in coding exon 2 of the TMCO1 gene, results from … (more)
The alteration results in a premature stop codon: _x000D_ _x000D_ The c.139_140delAG (p.S47*) alteration, located in coding exon 2 of the TMCO1 gene, results from the deletion of 2 nucleotides from position 139 to 140, causing a translational frameshift with a predicted alternate stop codon at amino acid position 47. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. The alteration is rare in population databases: _x000D_ _x000D_ Based on data from the Genome Aggregation Database (gnomAD), the c.139_140delAG alteration was observed in 0.0103% (29/282,676) of total alleles studied. No homozygotes were reported in gnomAD. The alteration has been observed in affected individuals:_x000D_ _x000D_ The c.139_140delAG (p.S47*) alteration in TMCO1 has been reported homozygous in multiple patients of different ethnicities with cerebrofaciothoracic dysplasia (Xin, 2010; Yates, 2019). Based on the available evidence, this alteration is classified as pathogenic. (less)
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Pathogenic
(Jan 05, 2010)
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no assertion criteria provided
Method: literature only
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CRANIOFACIAL DYSMORPHISM, SKELETAL ANOMALIES, AND IMPAIRED INTELLECTUAL DEVELOPMENT SYNDROME 1
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000045387.7
First in ClinVar: Apr 04, 2013 Last updated: Jul 23, 2022 |
Comment on evidence:
Sharkia et al. (2019) noted that this mutation is designated c.292_293del (c.292_293del, NM_019026.4), ser98-to-ter (S98X), based on the updated sequence. In 9 Amish patients from … (more)
Sharkia et al. (2019) noted that this mutation is designated c.292_293del (c.292_293del, NM_019026.4), ser98-to-ter (S98X), based on the updated sequence. In 9 Amish patients from northeastern Ohio with craniofacial dysmorphism, skeletal anomalies, and impaired intellectual development syndrome (CFSMR1; 213980), Xin et al. (2010) identified a homozygous 2-bp deletion (c.139delAG, NM_019026) in exon 2 of the TMCO1 gene, resulting in a frameshift and premature termination at codon 47. Screening of ethnically matched controls from the same community showed a carrier frequency of 0.7%. Screening of Amish from southeastern Pennsylvania yielded a carrier frequency of 6.6%. Further analysis identified 6 homozygous carriers from Pennsylvania who had a similar phenotype. In 4 patients with CFSMR1, including 3 brothers from a consanguineous Pakistani family and an unrelated boy from a nonconsanguineous Scottish family, Yates et al. (2019) identified homozygosity for this 2-bp deletion in the TMCO1 gene, which they cited as c.292_293del, resulting in a ser98-to-ter (S98X) substitution. The mutation was identified by whole-exome and/or Sanger sequencing. (less)
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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A novel biallelic loss-of-function mutation in TMCO1 gene confirming and expanding the phenotype spectrum of cerebro-facio-thoracic dysplasia. | Sharkia R | American journal of medical genetics. Part A | 2019 | PMID: 31102500 |
Cerebrofaciothoracic dysplasia: Four new patients with a recurrent TMCO1 pathogenic variant. | Michael Yates T | American journal of medical genetics. Part A | 2019 | PMID: 30556256 |
Whole-exome sequencing links TMCO1 defect syndrome with cerebro-facio-thoracic dysplasia. | Pehlivan D | European journal of human genetics : EJHG | 2014 | PMID: 24424126 |
TMCO1 deficiency causes autosomal recessive cerebrofaciothoracic dysplasia. | Alanay Y | American journal of medical genetics. Part A | 2014 | PMID: 24194475 |
Whole-exome sequencing identified a patient with TMCO1 defect syndrome and expands the phenotic spectrum. | Caglayan AO | Clinical genetics | 2013 | PMID: 23320496 |
Homozygous frameshift mutation in TMCO1 causes a syndrome with craniofacial dysmorphism, skeletal anomalies, and mental retardation. | Xin B | Proceedings of the National Academy of Sciences of the United States of America | 2010 | PMID: 20018682 |
Text-mined citations for rs752176040 ...
HelpRecord last updated May 19, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.