ClinVar Genomic variation as it relates to human health
NM_182916.3(TRNT1):c.668T>C (p.Ile223Thr)
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_182916.3(TRNT1):c.668T>C (p.Ile223Thr)
Variation ID: 157614 Accession: VCV000157614.15
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p26.2 3: 3146489 (GRCh38) [ NCBI UCSC ] 3: 3188173 (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 Jul 16, 2015 Apr 15, 2024 Oct 11, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_182916.3:c.668T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_886552.3:p.Ile223Thr missense NM_001302946.2:c.668T>C NP_001289875.2:p.Ile223Thr missense NM_001367321.1:c.668T>C NP_001354250.1:p.Ile223Thr missense NM_001367322.1:c.668T>C NP_001354251.1:p.Ile223Thr missense NM_001367323.1:c.668T>C NP_001354252.1:p.Ile223Thr missense NR_159934.1:n.746T>C non-coding transcript variant NR_159935.1:n.746T>C non-coding transcript variant NR_159937.1:n.1788T>C non-coding transcript variant NR_159939.1:n.607T>C non-coding transcript variant NR_159940.1:n.621T>C non-coding transcript variant NR_159941.1:n.1788T>C non-coding transcript variant NC_000003.12:g.3146489T>C NC_000003.11:g.3188173T>C NG_041800.2:g.24574T>C LRG_1314:g.24574T>C LRG_1314t1:c.668T>C LRG_1314p1:p.Ile223Thr Q96Q11:p.Ile223Thr - Protein change
- I223T
- Other names
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- Canonical SPDI
- NC_000003.12:3146488:T:C
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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
Help
The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00003
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
The Genome Aggregation Database (gnomAD) 0.00008
Trans-Omics for Precision Medicine (TOPMed) 0.00008
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 | ||
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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
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. |
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TRNT1 | - | - |
GRCh38 GRCh37 |
550 | 677 |
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. |
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Pathogenic (2) |
criteria provided, single submitter
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Oct 11, 2023 | RCV000144947.8 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Sep 1, 2023 | RCV000734561.11 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 22, 2023 | RCV003415973.4 |
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. |
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Pathogenic
(Aug 08, 2018)
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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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Eurofins Ntd Llc (ga)
Accession: SCV000862713.1
First in ClinVar: Dec 16, 2018 Last updated: Dec 16, 2018 |
Number of individuals with the variant: 1
Sex: mixed
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Pathogenic
(Sep 07, 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: SCV002072691.2
First in ClinVar: Feb 04, 2022 Last updated: Jan 21, 2023 |
Comment:
Published functional studies found this variant is associated with significantly reduced enzyme activity and stability (Leibovitch M et al., 2018); Not observed at a significant … (more)
Published functional studies found this variant is associated with significantly reduced enzyme activity and stability (Leibovitch M et al., 2018); Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29358286, 27370603, 25193871, 31555444, 31338833, 29055896, 29454993) (less)
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Pathogenic
(Mar 22, 2023)
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criteria provided, single submitter
Method: clinical testing
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TRNT1-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004107155.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The TRNT1 c.668T>C variant is predicted to result in the amino acid substitution p.Ile223Thr. This variant has been reported in the compound heterozygous and homozygous … (more)
The TRNT1 c.668T>C variant is predicted to result in the amino acid substitution p.Ile223Thr. This variant has been reported in the compound heterozygous and homozygous states in individuals with sideroblastic anemia with immunodeficiency, fevers, and developmental delay (SIFD) (Chakraborty et al. 2014. PubMed ID: 25193871; Wedatilake et al. 2016. PubMed ID: 2737060; Barton et al. 2018. PubMed ID: 29055896; Giannelou et al. 2018. PubMed ID: 29358286; Jfri et al. 2019. PubMed ID: 31555444). Of note, in addition to the clinical features typically associated with SIFD, metabolic features and severe fetal hydrops and neonatal anemia were also reported in cases of SIFD (Wedatilake et al. 2016. PubMed ID: 2737060; Barton et al. 2018. PubMed ID: 29055896). A functional study showed that that c.668T>C (p.Ile223Thr) variant impacts protein function (Leibovitch et al. 2018. PubMed ID: 29454993). This variant is reported in 0.0077% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/3-3188173-T-C). This variant is interpreted as pathogenic. (less)
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Pathogenic
(Oct 11, 2023)
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criteria provided, single submitter
Method: clinical testing
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Congenital sideroblastic anemia-B-cell immunodeficiency-periodic fever-developmental delay syndrome
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV001409298.4
First in ClinVar: Jul 16, 2020 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 223 of the TRNT1 protein (p.Ile223Thr). … (more)
This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 223 of the TRNT1 protein (p.Ile223Thr). This variant is present in population databases (rs370011798, gnomAD 0.009%). This missense change has been observed in individual(s) with sideroblastic anemia with B-cell immunodeficiency, periodic fevers, and developmental delay (PMID: 25193871, 27370603, 29055896, 29358286). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 157614). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TRNT1 protein function. Experimental studies have shown that this missense change affects TRNT1 function (PMID: 25193871, 29454993). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Sep 01, 2023)
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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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV004042158.5
First in ClinVar: Oct 14, 2023 Last updated: Apr 15, 2024 |
Comment:
TRNT1: PM3:Strong, PM1, PM2, PM5, PS3:Supporting
Number of individuals with the variant: 1
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Pathogenic
(Oct 30, 2014)
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no assertion criteria provided
Method: literature only
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SIDEROBLASTIC ANEMIA WITH B-CELL IMMUNODEFICIENCY, PERIODIC FEVERS, AND DEVELOPMENTAL DELAY
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000191963.2
First in ClinVar: Nov 15, 2014 Last updated: Jul 16, 2015 |
Comment on evidence:
In a Caucasian Hispanic patient, born of consanguineous parents, with sideroblastic anemia with B-cell immunodeficiency, periodic fevers, and developmental delay (SIFD; 616084), Chakraborty et al. … (more)
In a Caucasian Hispanic patient, born of consanguineous parents, with sideroblastic anemia with B-cell immunodeficiency, periodic fevers, and developmental delay (SIFD; 616084), Chakraborty et al. (2014) identified a homozygous c.668T-C transition in exon 6 of the TRNT1 gene, resulting in an ile223-to-thr (I223T) substitution at a highly conserved residue in the active site. The mutation, which was found by linkage analysis and candidate gene sequencing, was found at a very low frequency (0.0077%) in the Exome Sequencing Project database. In vitro functional expression studies showed that the missense I223T mutant could only partially rescue the growth defect in a yeast strain with a defective ortholog of TRNT1 (cca1), consistent with a partial loss of function. Direct sequencing of subsequent patients with the disorder found that 5 unrelated patients of Caucasian or Afro-Caribbean origin were compound heterozygous for I223T and another pathogenic mutation (see, e.g., 612907.0003 and 612907.0006). (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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In vitro studies of disease-linked variants of human tRNA nucleotidyltransferase reveal decreased thermal stability and altered catalytic activity. | Leibovitch M | Biochimica et biophysica acta. Proteins and proteomics | 2018 | PMID: 29454993 |
Aberrant tRNA processing causes an autoinflammatory syndrome responsive to TNF inhibitors. | Giannelou A | Annals of the rheumatic diseases | 2018 | PMID: 29358286 |
SIFD as a novel cause of severe fetal hydrops and neonatal anaemia with iron loading and marked extramedullary haemopoiesis. | Barton C | Journal of clinical pathology | 2018 | PMID: 29055896 |
TRNT1 deficiency: clinical, biochemical and molecular genetic features. | Wedatilake Y | Orphanet journal of rare diseases | 2016 | PMID: 27370603 |
Mutations in TRNT1 cause congenital sideroblastic anemia with immunodeficiency, fevers, and developmental delay (SIFD). | Chakraborty PK | Blood | 2014 | PMID: 25193871 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=TRNT1 | - | - | - | - |
Text-mined citations for rs370011798 ...
HelpRecord last updated Apr 15, 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.