ClinVar Genomic variation as it relates to human health
NM_018965.4(TREM2):c.97C>T (p.Gln33Ter)
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_018965.4(TREM2):c.97C>T (p.Gln33Ter)
Variation ID: 5219 Accession: VCV000005219.10
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 6p21.1 6: 41161557 (GRCh38) [ NCBI UCSC ] 6: 41129295 (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 Oct 5, 2015 May 1, 2024 May 3, 2022 - HGVS
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Nucleotide Protein Molecular
consequenceNM_018965.4:c.97C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_061838.1:p.Gln33Ter nonsense NM_001271821.2:c.97C>T NP_001258750.1:p.Gln33Ter nonsense NC_000006.12:g.41161557G>A NC_000006.11:g.41129295G>A NG_011561.1:g.6628C>T LRG_631:g.6628C>T LRG_631t1:c.97C>T LRG_631p1:p.Gln33Ter - Protein change
- Q33*
- Other names
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- Canonical SPDI
- NC_000006.12:41161556: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
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The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00002
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
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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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TREM2 | - | - |
GRCh38 GRCh37 |
164 | 172 |
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
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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 (3) |
no assertion criteria provided
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Mar 14, 2016 | RCV000005529.15 | |
Pathogenic (2) |
criteria provided, single submitter
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Oct 17, 2019 | RCV000721927.10 | |
Pathogenic (1) |
criteria provided, single submitter
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May 3, 2022 | RCV004018565.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Apr 21, 2022 | RCV002512810.9 |
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
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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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Pathogenic
(Oct 17, 2019)
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criteria provided, single submitter
Method: curation
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Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy 2
Affected status: unknown
Allele origin:
unknown
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SIB Swiss Institute of Bioinformatics
Accession: SCV001146845.1
First in ClinVar: Jan 20, 2020 Last updated: Jan 20, 2020 |
Comment:
This variant is interpreted as Pathogenic for Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy 2 , autosomal recessive. The following ACMG Tag(s) were applied: PM2, PP1, … (more)
This variant is interpreted as Pathogenic for Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy 2 , autosomal recessive. The following ACMG Tag(s) were applied: PM2, PP1, PM3, PS3, PVS1-Strong. (less)
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Pathogenic
(May 03, 2022)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV004970658.1
First in ClinVar: May 01, 2024 Last updated: May 01, 2024 |
Comment:
The c.97C>T (p.Q33*) alteration, located in exon 2 (coding exon 2) of the TREM2 gene, consists of a C to T substitution at nucleotide position … (more)
The c.97C>T (p.Q33*) alteration, located in exon 2 (coding exon 2) of the TREM2 gene, consists of a C to T substitution at nucleotide position 97. This changes the amino acid from a glutamine (Q) to a stop codon at amino acid position 33. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from gnomAD, the T allele has an overall frequency of 0.002% (5/248072) total alleles studied. The highest observed frequency was 0.005% (5/110958) of European (non-Finnish) alleles. This alteration has been detected in the homozygous state in multiple unrelated individuals with TREM2-related polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy. It has also been found to cosegregate among affected homozygous siblings (Coomans, 2018; Guerreiro, 2013; Bock, 2013; Soragna, 2003). Based on the available evidence, this alteration is classified as pathogenic. (less)
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Pathogenic
(Apr 21, 2022)
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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: SCV003439332.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Gln33*) in the TREM2 gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Gln33*) in the TREM2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TREM2 are known to be pathogenic (PMID: 12080485, 12754369, 12883936, 12925681, 23318515, 23582655). This variant is present in population databases (rs104894002, gnomAD 0.006%). This premature translational stop signal has been observed in individuals with autosomal recessive TREM2-related conditions (PMID: 12754369, 23318515). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 5219). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects TREM2 function (PMID: 25615530). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy 1
Affected status: yes
Allele origin:
germline
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Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV000734498.1 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018 |
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Pathogenic
(May 10, 2005)
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no assertion criteria provided
Method: literature only
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POLYCYSTIC LIPOMEMBRANOUS OSTEODYSPLASIA WITH SCLEROSING LEUKOENCEPHALOPATHY 2
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000025711.5
First in ClinVar: Apr 04, 2013 Last updated: Nov 25, 2018 |
Comment on evidence:
In 2 Belgian sibs with polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL2; 618193), Klunemann et al. (2005) identified a homozygous 97C-T transition in exon 2 … (more)
In 2 Belgian sibs with polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL2; 618193), Klunemann et al. (2005) identified a homozygous 97C-T transition in exon 2 of the TREM2 gene, resulting in a gln33-to-ter (Q33X) substitution and premature termination of the protein. (less)
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Pathogenic
(Mar 14, 2016)
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no assertion criteria provided
Method: clinical testing
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Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy 1
Affected status: yes
Allele origin:
germline
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Genome Diagnostics Laboratory, Amsterdam University Medical Center
Study: VKGL Data-share Consensus
Accession: SCV000745890.1 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018 |
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not provided
(-)
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no classification provided
Method: literature only
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Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy 1
Affected status: yes
Allele origin:
germline
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GeneReviews
Accession: SCV000223801.2
First in ClinVar: Oct 05, 2015 Last updated: Oct 01, 2022 |
Comment:
This variant has been reported to cause a PLOSL with typical bone pathology on radiologic examination but also a frontotemporal dementia-like syndrome without bone pathology … (more)
This variant has been reported to cause a PLOSL with typical bone pathology on radiologic examination but also a frontotemporal dementia-like syndrome without bone pathology on radiographs. (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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Polycystic Lipomembranous Osteodysplasia with Sclerosing Leukoencephalopathy. | Adam MP | - | 2020 | PMID: 20301376 |
Early-onset dementia, leukoencephalopathy and brain calcifications: a clinical, imaging and pathological comparison of ALSP and PLOSL/Nasu Hakola disease. | Coomans C | Acta neurologica Belgica | 2018 | PMID: 30242731 |
Evidence of CNS β-amyloid deposition in Nasu-Hakola disease due to the TREM2 Q33X mutation. | Ghezzi L | Neurology | 2017 | PMID: 29142083 |
Disease-Associated Mutations of TREM2 Alter the Processing of N-Linked Oligosaccharides in the Golgi Apparatus. | Park JS | Traffic (Copenhagen, Denmark) | 2015 | PMID: 25615530 |
Variants in triggering receptor expressed on myeloid cells 2 are associated with both behavioral variant frontotemporal lobar degeneration and Alzheimer's disease. | Giraldo M | Neurobiology of aging | 2013 | PMID: 23582655 |
Polycystic Lipomembranous Osteodysplasia with Sclerosing Leukoencephalopathy (PLOSL): a new report of an Italian woman and review of the literature. | Bock V | Journal of the neurological sciences | 2013 | PMID: 23399524 |
Using exome sequencing to reveal mutations in TREM2 presenting as a frontotemporal dementia-like syndrome without bone involvement. | Guerreiro RJ | JAMA neurology | 2013 | PMID: 23318515 |
The genetic causes of basal ganglia calcification, dementia, and bone cysts: DAP12 and TREM2. | Klünemann HH | Neurology | 2005 | PMID: 15883308 |
DAP12/TREM2 deficiency results in impaired osteoclast differentiation and osteoporotic features. | Paloneva J | The Journal of experimental medicine | 2003 | PMID: 12925681 |
An Italian family with Nasu-Hakola disease. | Salmaggi A | Journal of neurology | 2003 | PMID: 12883936 |
An Italian family affected by Nasu-Hakola disease with a novel genetic mutation in the TREM2 gene. | Soragna D | Journal of neurology, neurosurgery, and psychiatry | 2003 | PMID: 12754369 |
Mutations in two genes encoding different subunits of a receptor signaling complex result in an identical disease phenotype. | Paloneva J | American journal of human genetics | 2002 | PMID: 12080485 |
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Text-mined citations for rs104894002 ...
HelpRecord last updated Jun 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.