ClinVar Genomic variation as it relates to human health
NM_006019.4(TCIRG1):c.702del (p.Ile235fs)
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_006019.4(TCIRG1):c.702del (p.Ile235fs)
Variation ID: 2412722 Accession: VCV002412722.2
- Type and length
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Deletion, 1 bp
- Location
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Cytogenetic: 11q13.2 11: 68043642 (GRCh38) [ NCBI UCSC ] 11: 67811109 (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 Feb 8, 2023 Jul 23, 2024 Jul 17, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_006019.4:c.702del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_006010.2:p.Ile235fs frameshift NM_001351059.2:c.-209del 5 prime UTR NM_006019.3:c.702delG NM_006053.4:c.54del NP_006044.1:p.Ile19fs frameshift NC_000011.10:g.68043642del NC_000011.9:g.67811109del NG_007878.1:g.9627del LRG_115:g.9627del LRG_115t1:c.702del LRG_115p1:p.Ile235Serfs - Protein change
- I19fs, I235fs
- Other names
- NM_006053.4:c.54del
- Canonical SPDI
- NC_000011.10:68043641:G:
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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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- Links
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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TCIRG1 | - | - |
GRCh38 GRCh37 |
1447 | 1472 |
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
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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/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jul 17, 2023 | RCV002789996.4 |
Submissions - Germline
Classification
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The submitted germline classification for each SCV record. (Last evaluated) |
Review status
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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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Likely pathogenic
(Jan 25, 2023)
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criteria provided, single submitter
Method: curation
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Autosomal recessive osteopetrosis 1
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
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Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Accession: SCV003761313.1
First in ClinVar: Feb 07, 2023 Last updated: Feb 07, 2023 |
Comment:
The homozygous p.Ile235SerfsTer44 variant in TCIRG1 was identified by our study in one individual with osteopetrosis. The p.Ile235SerfsTer44 variant in TCIRG1 has been previously reported … (more)
The homozygous p.Ile235SerfsTer44 variant in TCIRG1 was identified by our study in one individual with osteopetrosis. The p.Ile235SerfsTer44 variant in TCIRG1 has been previously reported in 3 individuals with autosomal recessive osteopetrosis 1 (PMID: 17400532, PMID: 15300850). These 3 affected individuals were homozygotes (PMID: 17400532, PMID: 15300850), which increases the likelihood that the p.Ile235SerfsTer44 variant is pathogenic. This variant was absent from large population studies. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 235 and leads to a premature termination codon 44 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the TCIRG1 gene is strongly associated to autosomal recessive osteopetrosis 1. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive osteopetrosis 1. ACMG/AMP Criteria applied: PVS1_Strong, PM2_Supporting, PM3 (Richards 2015). (less)
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Pathogenic
(Jul 17, 2023)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive osteopetrosis 1
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV005087203.1
First in ClinVar: Jul 23, 2024 Last updated: Jul 23, 2024 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism … (more)
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with autosomal recessive osteopetrosis 1 (MIM#259700). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Patients may present with variable features (PMID: 17400532). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0701 - Other variants predicted to cause NMD comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. It has been reported in at least three unrelated families with osteopetrosis (PMIDs: 15300850, 17400532). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1206 - This variant has been shown to be paternally inherited (by segregation analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (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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Molecular study of six families originating from the Middle-East and presenting with autosomal recessive osteopetrosis. | Souraty N | European journal of medical genetics | 2007 | PMID: 17400532 |
TCIRG1-dependent recessive osteopetrosis: mutation analysis, functional identification of the splicing defects, and in vitro rescue by U1 snRNA. | Susani L | Human mutation | 2004 | PMID: 15300850 |
Text-mined citations for this variant ...
HelpRecord last updated Jul 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.