ClinVar Genomic variation as it relates to human health
NM_006019.4(TCIRG1):c.2236+1G>A
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.2236+1G>A
Variation ID: 558226 Accession: VCV000558226.16
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11q13.2 11: 68050255 (GRCh38) [ NCBI UCSC ] 11: 67817722 (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 Aug 5, 2018 Feb 14, 2024 Nov 24, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_006019.4:c.2236+1G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
splice donor NM_001351059.2:c.1342+1G>A splice donor NM_006053.4:c.1588+1G>A splice donor NC_000011.10:g.68050255G>A NC_000011.9:g.67817722G>A NG_007878.1:g.16240G>A NG_123127.1:g.427G>A LRG_115:g.16240G>A - Protein change
- Other names
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- Canonical SPDI
- NC_000011.10:68050254:G:A
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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.
The Genome Aggregation Database (gnomAD), exomes 0.00000
Trans-Omics for Precision Medicine (TOPMed) 0.00002
The Genome Aggregation Database (gnomAD) 0.00004
- 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 | ||
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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
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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TCIRG1 | - | - |
GRCh38 GRCh37 |
1430 | 1455 |
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 (6) |
criteria provided, multiple submitters, no conflicts
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Oct 17, 2023 | RCV000674460.10 | |
Pathogenic (1) |
criteria provided, single submitter
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Nov 24, 2023 | RCV001062506.5 |
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
(May 07, 2018)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive osteopetrosis 1
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000799799.1
First in ClinVar: Aug 05, 2018 Last updated: Aug 05, 2018 |
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Pathogenic
(Nov 01, 2018)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive osteopetrosis 1
Affected status: yes
Allele origin:
germline
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Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV001428496.1
First in ClinVar: Aug 16, 2020 Last updated: Aug 16, 2020 |
Comment:
This variant was identified as homozygous
Number of individuals with the variant: 1
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Pathogenic
(Mar 05, 2022)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive osteopetrosis 1
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002786488.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Oct 17, 2023)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive osteopetrosis 1
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004205728.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Sep 06, 2021)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive osteopetrosis 1
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV002018946.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Nov 24, 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: SCV001227312.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change affects a donor splice site in intron 18 of the TCIRG1 gene. It is expected to disrupt RNA splicing. Variants that disrupt … (more)
This sequence change affects a donor splice site in intron 18 of the TCIRG1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in TCIRG1 are known to be pathogenic (PMID: 10888887, 10942435, 11532986, 19448635). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with osteopetrosis (PMID: 11532986, 12552563, 20424301, 25018813, 31319225). 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. This variant is also known as G11279A or IVS18+1G>A. ClinVar contains an entry for this variant (Variation ID: 558226). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Dec 11, 2020)
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no assertion criteria provided
Method: clinical testing
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Infantile malignant osteopetrosis
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV002092936.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
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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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Clinical utility of a targeted next generation sequencing panel in severe and pediatric onset Mendelian diseases. | Isik E | European journal of medical genetics | 2019 | PMID: 31319225 |
Malignant infantile osteopetrosis: case report with review of literature. | Essabar L | The Pan African medical journal | 2014 | PMID: 25018813 |
Novel mutations in Indian patients with autosomal recessive infantile malignant osteopetrosis. | Phadke SR | The Indian journal of medical research | 2010 | PMID: 20424301 |
Impaired gastric acidification negatively affects calcium homeostasis and bone mass. | Schinke T | Nature medicine | 2009 | PMID: 19448635 |
Splicing in action: assessing disease causing sequence changes. | Baralle D | Journal of medical genetics | 2005 | PMID: 16199547 |
Novel mutations in the TCIRG1 gene encoding the a3 subunit of the vacuolar proton pump in patients affected by infantile malignant osteopetrosis. | Scimeca JC | Human mutation | 2003 | PMID: 12552563 |
The mutational spectrum of human malignant autosomal recessive osteopetrosis. | Sobacchi C | Human molecular genetics | 2001 | PMID: 11532986 |
Mutations in the a3 subunit of the vacuolar H(+)-ATPase cause infantile malignant osteopetrosis. | Kornak U | Human molecular genetics | 2000 | PMID: 10942435 |
Defects in TCIRG1 subunit of the vacuolar proton pump are responsible for a subset of human autosomal recessive osteopetrosis. | Frattini A | Nature genetics | 2000 | PMID: 10888887 |
Text-mined citations for rs1475338876 ...
HelpRecord last updated Mar 17, 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.