ClinVar Genomic variation as it relates to human health
NM_033453.4(ITPA):c.359_366dup (p.Gly123fs)
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_033453.4(ITPA):c.359_366dup (p.Gly123fs)
Variation ID: 218091 Accession: VCV000218091.25
- Type and length
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Duplication, 8 bp
- Location
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Cytogenetic: 20p13 20: 3218578-3218579 (GRCh38) [ NCBI UCSC ] 20: 3199224-3199225 (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 Nov 22, 2015 May 12, 2024 Oct 22, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_033453.4:c.359_366dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_258412.1:p.Gly123fs frameshift NM_001267623.2:c.236_243dup NP_001254552.1:p.Gly82fs frameshift NM_001324236.2:c.22_29dup NP_001311165.1:p.Gly11fs frameshift NM_001324237.2:c.22_29dup NP_001311166.1:p.Gly11fs frameshift NM_001324238.2:c.22_29dup NP_001311167.1:p.Gly11fs frameshift NM_001324240.2:c.359_366dup NP_001311169.1:p.Gly123fs frameshift NM_001351739.2:c.22_29dup NP_001338668.1:p.Gly11fs frameshift NM_033453.3:c.359_366dupTCAGCACC NM_181493.4:c.308_315dup NP_852470.1:p.Gly106fs frameshift NR_052000.2:n.586_593dup non-coding transcript variant NR_052002.2:n.348_355dup non-coding transcript variant NC_000020.11:g.3218580_3218587dup NC_000020.10:g.3199226_3199233dup NG_012093.2:g.14714_14721dup - Protein change
- G106fs, G82fs, G11fs, G123fs
- Other names
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- Canonical SPDI
- NC_000020.11:3218578:CTCAGCACC:CTCAGCACCTCAGCACC
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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
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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ITPA | - | - |
GRCh38 GRCh37 |
265 | 355 |
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
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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 (4) |
criteria provided, multiple submitters, no conflicts
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Oct 5, 2021 | RCV000202316.13 | |
Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Nov 1, 2022 | RCV001008848.10 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 22, 2023 | RCV001070704.6 | |
Pathogenic (1) |
criteria provided, single submitter
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- | RCV001526600.3 |
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
(-)
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criteria provided, single submitter
Method: research
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Developmental and epileptic encephalopathy, 35
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
paternal
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TIDEX, University of British Columbia
Accession: SCV000586836.1
First in ClinVar: May 31, 2018 Last updated: May 31, 2018 |
Sex: female
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Pathogenic
(Dec 13, 2017)
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criteria provided, single submitter
Method: clinical testing
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Developmental and epileptic encephalopathy, 35
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
inherited
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Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München
Accession: SCV000680264.1
First in ClinVar: Nov 23, 2015 Last updated: Nov 23, 2015 |
Sex: male
Tissue: blood
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Likely pathogenic
(Aug 06, 2018)
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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: SCV001168653.1
First in ClinVar: Mar 16, 2020 Last updated: Mar 16, 2020 |
Comment:
The c.359_366dupTCAGCAC variant in the ITPA gene has been reported previously, in the homozygous state, in an individual with early onset encephalopathy who had 2.9% … (more)
The c.359_366dupTCAGCAC variant in the ITPA gene has been reported previously, in the homozygous state, in an individual with early onset encephalopathy who had 2.9% residual ITPA enzyme activity compared to wild type controls (Kevelam et al., 2015). This variant was also reported in the heterozygous state in a healthy individual who had 30% residual ITPA enzyme activity compared to wild type controls (Atanasova et al., 2007). The c.359_366dupTCAGCAC variant causes a frameshift starting with codon Glycine 123, changes this amino acid to a Serine residue, and creates a premature Stop codon at position 104 of the new reading frame, denoted p.Gly123SerfsX104. This variant is predicted to cause loss of normal protein function as the last 72 amino acids are lost and replaced with 103 incorrect amino acids. The c.359_366dupTCAGCAC variant is observed in 6/125,736 (0.005%) alleles from individuals of European background, in large population cohorts (Lek et al., 2016). (less)
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Partial congenital absence of teeth
Affected status: yes
Allele origin:
inherited
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Equipe Genetique des Anomalies du Developpement, Université de Bourgogne
Accession: SCV001737029.1
First in ClinVar: Jun 19, 2021 Last updated: Jun 19, 2021
Comment:
Homozygous, both variants are inherited from each parent
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Pathogenic
(Oct 05, 2021)
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criteria provided, single submitter
Method: clinical testing
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Developmental and epileptic encephalopathy, 35
Affected status: yes
Allele origin:
germline
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Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center
Accession: SCV002061613.2
First in ClinVar: Jan 22, 2022 Last updated: Feb 11, 2022 |
Comment:
PVS1, PS3, PM2
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Pathogenic
(Oct 22, 2023)
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criteria provided, single submitter
Method: clinical testing
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Inosine triphosphatase deficiency
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV001235971.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change results in a frameshift in the ITPA gene (p.Gly123Serfs*104). While this is not anticipated to result in nonsense mediated decay, it is … (more)
This sequence change results in a frameshift in the ITPA gene (p.Gly123Serfs*104). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 72 amino acid(s) of the ITPA protein and extend the protein by 31 additional amino acid residues. This variant is present in population databases (rs763029259, gnomAD 0.01%). This frameshift has been observed in individual(s) with ITPA-related conditions (PMID: 26224535). ClinVar contains an entry for this variant (Variation ID: 218091). This variant disrupts a region of the ITPA protein in which other variant(s) (p.Trp151*) have been determined to be pathogenic (PMID: 26224535, 30856165). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Nov 01, 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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV002821059.9
First in ClinVar: Jan 21, 2023 Last updated: May 12, 2024 |
Comment:
ITPA: PVS1, PM2, PM3
Number of individuals with the variant: 1
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Pathogenic
(Oct 01, 2015)
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no assertion criteria provided
Method: literature only
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DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 35
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000257323.1
First in ClinVar: Nov 22, 2015 Last updated: Nov 22, 2015 |
Comment on evidence:
In a patient of Roma origin (family IV) with developmental and epileptic encephalopathy-35 (DEE35; 616647), Kevelam et al. (2015) identified a homozygous 8-bp duplication (c.359_366dupTCAGCACC, … (more)
In a patient of Roma origin (family IV) with developmental and epileptic encephalopathy-35 (DEE35; 616647), Kevelam et al. (2015) identified a homozygous 8-bp duplication (c.359_366dupTCAGCACC, NM_033453.3) in exon 6 of the ITPA gene, resulting in a frameshift (Gly123SerfsTer104), that would result in an extended protein of 225 amino acids instead of 194 amino acids. The mutation segregated with the disorder in the family and was not found in the dbSNP (build 137), 1000 Genomes Project, Exome Variant Server, or in-house control exome databases, but was reported in the heterozygous state in 1 Bulgarian control individual. Patient fibroblasts showed 2.9% residual ITPA activity without accumulation of ITP. The patient presented at birth with hypotonia and irritability. She developed refractory seizures at 5 months of age. (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
HelpText-mined citations for rs1407446171 ...
HelpRecord last updated May 12, 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.