This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
ClinVar Genomic variation as it relates to human health
NM_006949.4(STXBP2):c.568C>T (p.Arg190Cys)
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.
(8)
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.
Conflicting classifications of pathogenicity
Uncertain significance(5); Likely benign(1)
Uncertain significance(5); Likely benign(1)
8
criteria provided, conflicting classifications
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_006949.4(STXBP2):c.568C>T (p.Arg190Cys)
Variation ID: 417965 Accession: VCV000417965.50
- Type and length
-
single nucleotide variant, 1 bp
- Location
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Cytogenetic: 19p13.2 19: 7641843 (GRCh38) [ NCBI UCSC ] 19: 7706729 (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 23, 2017 Oct 20, 2024 Mar 19, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_006949.4:c.568C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_008880.2:p.Arg190Cys missense NM_001127396.3:c.559C>T NP_001120868.1:p.Arg187Cys missense NM_001272034.2:c.601C>T NP_001258963.1:p.Arg201Cys missense NR_073560.2:n.608C>T non-coding transcript variant NC_000019.10:g.7641843C>T NC_000019.9:g.7706729C>T NG_016709.1:g.9739C>T LRG_165:g.9739C>T LRG_165t1:c.568C>T - Protein change
- R190C, R187C, R201C
- Other names
- -
- Canonical SPDI
- NC_000019.10:7641842:C:T
-
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.
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0.00020 (T)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
1000 Genomes Project 30x 0.00016
1000 Genomes Project 0.00020
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00024
Trans-Omics for Precision Medicine (TOPMed) 0.00035
The Genome Aggregation Database (gnomAD) 0.00041
The Genome Aggregation Database (gnomAD), exomes 0.00048
Exome Aggregation Consortium (ExAC) 0.00067
- 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. |
|||
| STXBP2 | - | - |
GRCh38 GRCh37 |
1072 | 1192 | |
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. |
|---|---|---|---|---|
| Conflicting interpretations of pathogenicity (5) |
criteria provided, conflicting classifications
|
Jan 31, 2024 | RCV000477888.22 | |
| Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
|
Jun 11, 2018 | RCV000658815.28 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Mar 19, 2024 | RCV004526685.2 |
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. |
|
|---|---|---|---|---|---|
|
Uncertain significance
(Jun 11, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000861500.1
First in ClinVar: Jul 09, 2018 Last updated: Jul 09, 2018 |
Number of individuals with the variant: 1
Zygosity: Single Heterozygote
Sex: mixed
|
|
|
Uncertain significance
(May 26, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Familial hemophagocytic lymphohistiocytosis 5
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV001288653.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
|
|
|
Uncertain significance
(Mar 30, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Familial hemophagocytic lymphohistiocytosis 5
Affected status: unknown
Allele origin:
germline
|
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago
Accession: SCV000899004.2
First in ClinVar: Apr 25, 2019 Last updated: May 06, 2023 |
Comment:
STXBP2 NM_006949 exon 7 p.Arg190Cys (c.568C>T): This variant has been reported in the literature in 1 individual with hemophagocytic lymphohistiocytosis as a double heterozygote (Zhang … (more)
STXBP2 NM_006949 exon 7 p.Arg190Cys (c.568C>T): This variant has been reported in the literature in 1 individual with hemophagocytic lymphohistiocytosis as a double heterozygote (Zhang 2014 PMID:24916509). This variant is present in 0.2% (21/8488) of Ashkenazi Jewish alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs370053399). This variant is present in ClinVar (Variation ID:404841). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. (less)
|
|
|
Likely benign
(Jan 31, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Familial hemophagocytic lymphohistiocytosis 5
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000769113.7
First in ClinVar: Apr 23, 2017 Last updated: Feb 20, 2024 |
|
|
|
Uncertain significance
(Mar 19, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV005039758.2
First in ClinVar: May 07, 2024 Last updated: Jul 07, 2024 |
Comment:
Variant summary: STXBP2 c.568C>T (p.Arg190Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging … (more)
Variant summary: STXBP2 c.568C>T (p.Arg190Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00048 in 157426 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in STXBP2 causing Familial Hemophagocytic Lymphohistiocytosis (0.00048 vs 0.0022), allowing no conclusion about variant significance. c.568C>T has been reported in the literature in heterozygous individuals affected with Familial Hemophagocytic Lymphohistiocytosis (e.g. Zhang_2014, Benavides_2020, Vinas-Gimenez_2021), and some were reported to also have variants in other genes. These reports do not provide unequivocal conclusions about association of the variant with Familial Hemophagocytic Lymphohistiocytosis. Publications report experimental evidence evaluating an impact on protein function, finding that the variant results in diminished degranulation and target cell apoptosis (Benavides_2020, Vinas-Gimenez_2021). However, this does not allow convincing conclusions about the variant effect. The following publications have been ascertained in the context of this evaluation (PMID: 24916509, 33162974, 34630398, 31286990, 37477760). ClinVar contains an entry for this variant (Variation ID: 417965). Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
|
|
|
Uncertain significance
(Dec 01, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV000780611.29
First in ClinVar: Jul 09, 2018 Last updated: Oct 20, 2024 |
Number of individuals with the variant: 1
|
|
|
Uncertain significance
(May 28, 2016)
|
no assertion criteria provided
Method: research
|
Familial hemophagocytic lymphohistiocytosis 5
Affected status: yes
Allele origin:
maternal
|
Division of Human Genetics, Children's Hospital of Philadelphia
Study: CSER-PediSeq
Accession: SCV000536933.1 First in ClinVar: Apr 23, 2017 Last updated: Apr 23, 2017 |
|
|
|
not provided
(-)
|
no classification provided
Method: literature only
|
Familial hemophagocytic lymphohistiocytosis 5
Affected status: unknown
Allele origin:
germline
|
GeneReviews
Accession: SCV001976574.2
First in ClinVar: Oct 08, 2021 Last updated: Oct 01, 2022 |
Comment:
Dominant-negative variant assoc w/fHLH in 1 infant [Benavides et al 2020]
|
Comment:
Comment:
STXBP2 NM_006949 exon 7 p.Arg190Cys (c.568C>T): This variant has been reported in the literature in 1 individual with hemophagocytic lymphohistiocytosis as a double heterozygote (Zhang 2014 PMID:24916509). This variant is present in 0.2% (21/8488) of Ashkenazi Jewish alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs370053399). This variant is present in ClinVar (Variation ID:404841). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Comment:
Variant summary: STXBP2 c.568C>T (p.Arg190Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00048 in 157426 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in STXBP2 causing Familial Hemophagocytic Lymphohistiocytosis (0.00048 vs 0.0022), allowing no conclusion about variant significance. c.568C>T has been reported in the literature in heterozygous individuals affected with Familial Hemophagocytic Lymphohistiocytosis (e.g. Zhang_2014, Benavides_2020, Vinas-Gimenez_2021), and some were reported to also have variants in other genes. These reports do not provide unequivocal conclusions about association of the variant with Familial Hemophagocytic Lymphohistiocytosis. Publications report experimental evidence evaluating an impact on protein function, finding that the variant results in diminished degranulation and target cell apoptosis (Benavides_2020, Vinas-Gimenez_2021). However, this does not allow convincing conclusions about the variant effect. The following publications have been ascertained in the context of this evaluation (PMID: 24916509, 33162974, 34630398, 31286990, 37477760). ClinVar contains an entry for this variant (Variation ID: 417965). Based on the evidence outlined above, the variant was classified as uncertain significance.
Comment:
Dominant-negative variant assoc w/fHLH in 1 infant [Benavides et al 2020]
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 was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Comment:
STXBP2 NM_006949 exon 7 p.Arg190Cys (c.568C>T): This variant has been reported in the literature in 1 individual with hemophagocytic lymphohistiocytosis as a double heterozygote (Zhang 2014 PMID:24916509). This variant is present in 0.2% (21/8488) of Ashkenazi Jewish alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs370053399). This variant is present in ClinVar (Variation ID:404841). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Comment:
Variant summary: STXBP2 c.568C>T (p.Arg190Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00048 in 157426 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in STXBP2 causing Familial Hemophagocytic Lymphohistiocytosis (0.00048 vs 0.0022), allowing no conclusion about variant significance. c.568C>T has been reported in the literature in heterozygous individuals affected with Familial Hemophagocytic Lymphohistiocytosis (e.g. Zhang_2014, Benavides_2020, Vinas-Gimenez_2021), and some were reported to also have variants in other genes. These reports do not provide unequivocal conclusions about association of the variant with Familial Hemophagocytic Lymphohistiocytosis. Publications report experimental evidence evaluating an impact on protein function, finding that the variant results in diminished degranulation and target cell apoptosis (Benavides_2020, Vinas-Gimenez_2021). However, this does not allow convincing conclusions about the variant effect. The following publications have been ascertained in the context of this evaluation (PMID: 24916509, 33162974, 34630398, 31286990, 37477760). ClinVar contains an entry for this variant (Variation ID: 417965). Based on the evidence outlined above, the variant was classified as uncertain significance.
Comment:
Dominant-negative variant assoc w/fHLH in 1 infant [Benavides et al 2020]
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Immunologic and Genetic Contributors to CD46-Dependent Immune Dysregulation. | Meyer BJ | Journal of clinical immunology | 2023 | PMID: 37477760 |
| Case Report: Characterizing the Role of the STXBP2-R190C Monoallelic Mutation Found in a Patient With Hemophagocytic Syndrome and Langerhans Cell Histiocytosis. | Viñas-Giménez L | Frontiers in immunology | 2021 | PMID: 34630398 |
| STXBP2-R190C Variant in a Patient With Neonatal Hemophagocytic Lymphohistiocytosis (HLH) and G6PD Deficiency Reveals a Critical Role of STXBP2 Domain 2 on Granule Exocytosis. | Benavides N | Frontiers in immunology | 2020 | PMID: 33162974 |
| Scoping review of biological treatment of deficiency of interleukin-36 receptor antagonist (DITRA) in children and adolescents. | Hospach T | Pediatric rheumatology online journal | 2019 | PMID: 31286990 |
| Synergistic defects of different molecules in the cytotoxic pathway lead to clinical familial hemophagocytic lymphohistiocytosis. | Zhang K | Blood | 2014 | PMID: 24916509 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=STXBP2 | - | - | - | - |
Text-mined citations for rs370053399 ...
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 Oct 20, 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.