This variant is interpreted as Likely Pathogenic, for Combined oxidative phosphorylation deficiency 35, autosomal recessive. The following ACMG Tag(s) were applied: PM2-Supporting => PM2 downgraded in strength to Supporting. PVS1-Strong => PVS1 downgraded in strength to Strong. PP1 => Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (https://www.ncbi.nlm.nih.gov/pubmed/28185376).
ClinVar Genomic variation as it relates to human health
NM_017646.6(TRIT1):c.22C>T (p.Arg8Ter)
Germline
Classification
Help
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.
(7)
Help
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/Likely pathogenic
7
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_017646.6(TRIT1):c.22C>T (p.Arg8Ter)
Variation ID: 417684 Accession: VCV000417684.10
- Type and length
-
single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1p34.2 1: 39883470 (GRCh38) [ NCBI UCSC ] 1: 40349142 (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 Apr 21, 2017 Jun 9, 2024 Dec 8, 2023 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_017646.6:c.22C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_060116.2:p.Arg8Ter nonsense NM_001312691.1:c.22C>T NP_001299620.1:p.Arg8Ter nonsense NM_001312692.1:c.22C>T NP_001299621.1:p.Arg8Ter nonsense NR_132401.1:n.42C>T non-coding transcript variant NR_132402.1:n.42C>T non-coding transcript variant NR_132403.1:n.42C>T non-coding transcript variant NR_132404.1:n.42C>T non-coding transcript variant NR_132405.1:n.42C>T non-coding transcript variant NR_132406.1:n.42C>T non-coding transcript variant NR_132407.1:n.42C>T non-coding transcript variant NR_132408.1:n.42C>T non-coding transcript variant NR_132409.1:n.42C>T non-coding transcript variant NR_132410.1:n.42C>T non-coding transcript variant NR_132412.1:n.42C>T non-coding transcript variant NR_132413.1:n.42C>T non-coding transcript variant NR_132414.1:n.42C>T non-coding transcript variant NR_132415.1:n.42C>T non-coding transcript variant NC_000001.11:g.39883470G>A NC_000001.10:g.40349142G>A NG_042822.1:g.5042C>T - Protein change
- R8*
- Other names
- -
- Canonical SPDI
- NC_000001.11:39883469:G:A
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
Trans-Omics for Precision Medicine (TOPMed) 0.00010
Exome Aggregation Consortium (ExAC) 0.00015
- Links
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 | ||
|---|---|---|---|---|---|---|
| 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. |
|||
| MYCL-AS1 | - | - | - | GRCh38 | - | 41 |
| TRIT1 | - | - |
GRCh38 GRCh37 |
114 | 147 | |
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. |
|---|---|---|---|---|
| Uncertain significance (1) |
no assertion criteria provided
|
- | RCV000477658.1 | |
| Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Dec 8, 2023 | RCV000584740.2 | |
| Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
May 12, 2023 | RCV001796068.7 | |
| Likely pathogenic (1) |
criteria provided, single submitter
|
Sep 19, 2022 | RCV002526505.2 |
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. |
|
|---|---|---|---|---|---|
|
Likely pathogenic
(Oct 15, 2018)
|
criteria provided, single submitter
Method: curation
|
Combined oxidative phosphorylation deficiency 35
Affected status: unknown
Allele origin:
unknown
|
SIB Swiss Institute of Bioinformatics
Accession: SCV000883202.1
First in ClinVar: Feb 19, 2018 Last updated: Feb 19, 2018 |
Comment:
This variant is interpreted as Likely Pathogenic, for Combined oxidative phosphorylation deficiency 35, autosomal recessive. The following ACMG Tag(s) were applied: PM2-Supporting => PM2 downgraded … (more)
This variant is interpreted as Likely Pathogenic, for Combined oxidative phosphorylation deficiency 35, autosomal recessive. The following ACMG Tag(s) were applied: PM2-Supporting => PM2 downgraded in strength to Supporting. PVS1-Strong => PVS1 downgraded in strength to Strong. PP1 => Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (https://www.ncbi.nlm.nih.gov/pubmed/28185376). (less)
|
|
|
Likely pathogenic
(Dec 28, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV002032685.3
First in ClinVar: Dec 18, 2021 Last updated: Jan 07, 2023 |
Comment:
Identified in trans with a missense variant, in siblings with neurological disease in published literature (Kernohan et al., 2017); Nonsense variant predicted to result in … (more)
Identified in trans with a missense variant, in siblings with neurological disease in published literature (Kernohan et al., 2017); 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: 28185376, 32948376, 36049610, 36047296, 34052969) (less)
|
|
|
Pathogenic
(May 12, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV002243010.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 417684). This premature translational stop signal … (more)
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 417684). This premature translational stop signal has been observed in individual(s) with clinical features of combined oxidative phosphorylation deficiency (PMID: 28185376, 34052969). This variant is present in population databases (rs184469579, gnomAD 0.06%). This sequence change creates a premature translational stop signal (p.Arg8*) in the TRIT1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TRIT1 are known to be pathogenic (PMID: 24901367, 28185376). (less)
|
|
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Likely pathogenic
(Sep 19, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV003701496.2
First in ClinVar: Feb 07, 2023 Last updated: May 01, 2024 |
Comment:
The c.22C>T (p.R8*) alteration, located in exon 1 (coding exon 1) of the TRIT1 gene, consists of a C to T substitution at nucleotide position … (more)
The c.22C>T (p.R8*) alteration, located in exon 1 (coding exon 1) of the TRIT1 gene, consists of a C to T substitution at nucleotide position 22. This changes the amino acid from an arginine (R) to a stop codon at amino acid position 8. The predicted stop codon occurs within the first 150 nucleotides of the TRIT1 gene. This alteration may escape nonsense-mediated mRNA decay and/or be rescued by re-initiation (Rivas, 2015; Lindeboom, 2016; Rhee, 2017). However, the impacted region is critical for protein function (Ambry internal data). This variant has been confirmed in trans with another TRIT1 variant in two siblings with acquired microcephaly and seizures (Kernohan, 2017). Based on internal structural analysis, the N-terminal residues 1-56 of TRIT1 contain a mitochrondrial targeting sequence which is critical to full function of the protein (Yarham, 2014; Khalique, 2020). Based on the available evidence, this alteration is classified as likely pathogenic. (less)
|
|
|
Pathogenic
(Dec 08, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Combined oxidative phosphorylation deficiency 35
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV005049810.1
First in ClinVar: Jun 09, 2024 Last updated: Jun 09, 2024 |
|
|
|
Uncertain significance
(-)
|
no assertion criteria provided
Method: research
|
TRIT1 Deficiency
Affected status: yes
Allele origin:
inherited
|
Care4Rare-SOLVE, CHEO
Study: Care4Rare
Accession: SCV000564084.1 First in ClinVar: Apr 21, 2017 Last updated: Apr 21, 2017 |
Comment:
This variant was seen in a heterozygous state with c.856A>G.
Number of individuals with the variant: 1
Sex: female
|
|
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Pathogenic
(Feb 16, 2018)
|
no assertion criteria provided
Method: literature only
|
COMBINED OXIDATIVE PHOSPHORYLATION DEFICIENCY 35
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000692463.1
First in ClinVar: Feb 19, 2018 Last updated: Feb 19, 2018 |
Comment on evidence:
For discussion of the c.22C-T transition (c.22C-T, NM_017646.4) in the TRIT1 gene, resulting in an arg8-to-ter (R8X) substitution, that was found in compound heterozygous state … (more)
For discussion of the c.22C-T transition (c.22C-T, NM_017646.4) in the TRIT1 gene, resulting in an arg8-to-ter (R8X) substitution, that was found in compound heterozygous state in 2 sibs with combined oxidative phosphorylation deficiency-35 (COXPD35; 617873) by Kernohan et al. (2017), see 617840.0005. (less)
|
Comment:
Comment:
Identified in trans with a missense variant, in siblings with neurological disease in published literature (Kernohan et al., 2017); 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: 28185376, 32948376, 36049610, 36047296, 34052969)
Comment:
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 417684). This premature translational stop signal has been observed in individual(s) with clinical features of combined oxidative phosphorylation deficiency (PMID: 28185376, 34052969). This variant is present in population databases (rs184469579, gnomAD 0.06%). This sequence change creates a premature translational stop signal (p.Arg8*) in the TRIT1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TRIT1 are known to be pathogenic (PMID: 24901367, 28185376).
Comment:
The c.22C>T (p.R8*) alteration, located in exon 1 (coding exon 1) of the TRIT1 gene, consists of a C to T substitution at nucleotide position 22. This changes the amino acid from an arginine (R) to a stop codon at amino acid position 8. The predicted stop codon occurs within the first 150 nucleotides of the TRIT1 gene. This alteration may escape nonsense-mediated mRNA decay and/or be rescued by re-initiation (Rivas, 2015; Lindeboom, 2016; Rhee, 2017). However, the impacted region is critical for protein function (Ambry internal data). This variant has been confirmed in trans with another TRIT1 variant in two siblings with acquired microcephaly and seizures (Kernohan, 2017). Based on internal structural analysis, the N-terminal residues 1-56 of TRIT1 contain a mitochrondrial targeting sequence which is critical to full function of the protein (Yarham, 2014; Khalique, 2020). Based on the available evidence, this alteration is classified as likely pathogenic.
Comment:
This variant was seen in a heterozygous state with c.856A>G.
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:
This variant is interpreted as Likely Pathogenic, for Combined oxidative phosphorylation deficiency 35, autosomal recessive. The following ACMG Tag(s) were applied: PM2-Supporting => PM2 downgraded in strength to Supporting. PVS1-Strong => PVS1 downgraded in strength to Strong. PP1 => Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (https://www.ncbi.nlm.nih.gov/pubmed/28185376).
Comment:
Identified in trans with a missense variant, in siblings with neurological disease in published literature (Kernohan et al., 2017); 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: 28185376, 32948376, 36049610, 36047296, 34052969)
Comment:
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 417684). This premature translational stop signal has been observed in individual(s) with clinical features of combined oxidative phosphorylation deficiency (PMID: 28185376, 34052969). This variant is present in population databases (rs184469579, gnomAD 0.06%). This sequence change creates a premature translational stop signal (p.Arg8*) in the TRIT1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TRIT1 are known to be pathogenic (PMID: 24901367, 28185376).
Comment:
The c.22C>T (p.R8*) alteration, located in exon 1 (coding exon 1) of the TRIT1 gene, consists of a C to T substitution at nucleotide position 22. This changes the amino acid from an arginine (R) to a stop codon at amino acid position 8. The predicted stop codon occurs within the first 150 nucleotides of the TRIT1 gene. This alteration may escape nonsense-mediated mRNA decay and/or be rescued by re-initiation (Rivas, 2015; Lindeboom, 2016; Rhee, 2017). However, the impacted region is critical for protein function (Ambry internal data). This variant has been confirmed in trans with another TRIT1 variant in two siblings with acquired microcephaly and seizures (Kernohan, 2017). Based on internal structural analysis, the N-terminal residues 1-56 of TRIT1 contain a mitochrondrial targeting sequence which is critical to full function of the protein (Yarham, 2014; Khalique, 2020). Based on the available evidence, this alteration is classified as likely pathogenic.
Comment:
This variant was seen in a heterozygous state with c.856A>G.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Genetic and Clinical Predictors of Ataxia in Pediatric Primary Mitochondrial Disorders. | Martin-Saavedra JS | Cerebellum (London, England) | 2022 | PMID: 34052969 |
| Targeting mitochondrial and cytosolic substrates of TRIT1 isopentenyltransferase: Specificity determinants and tRNA-i6A37 profiles. | Khalique A | PLoS genetics | 2020 | PMID: 32324744 |
| Allelic imbalance of somatic mutations in cancer genomes and transcriptomes. | Rhee JK | Scientific reports | 2017 | PMID: 28490743 |
| Matchmaking facilitates the diagnosis of an autosomal-recessive mitochondrial disease caused by biallelic mutation of the tRNA isopentenyltransferase (TRIT1) gene. | Kernohan KD | Human mutation | 2017 | PMID: 28185376 |
| The rules and impact of nonsense-mediated mRNA decay in human cancers. | Lindeboom RG | Nature genetics | 2016 | PMID: 27618451 |
| Human genomics. Effect of predicted protein-truncating genetic variants on the human transcriptome. | Rivas MA | Science (New York, N.Y.) | 2015 | PMID: 25954003 |
| Defective i6A37 modification of mitochondrial and cytosolic tRNAs results from pathogenic mutations in TRIT1 and its substrate tRNA. | Yarham JW | PLoS genetics | 2014 | PMID: 24901367 |
Text-mined citations for rs184469579 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Sep 29, 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.