VCV000030219.29 - ClinVar

NM_006949.4(STXBP2):c.1621G>A (p.Gly541Ser)

Germline

Classification

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.

(13)

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.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_006949.4(STXBP2):c.1621G>A (p.Gly541Ser)

Variation ID: 30219 Accession: VCV000030219.29

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 19p13.2 19: 7647436 (GRCh38) [ NCBI UCSC ] 19: 7712322 (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 4, 2013	Oct 8, 2024	Mar 21, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_006949.4:c.1621G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_008880.2:p.Gly541Ser	missense
NM_001127396.3:c.1612G>A	NP_001120868.1:p.Gly538Ser	missense
NM_001272034.2:c.1654G>A	NP_001258963.1:p.Gly552Ser	missense
NR_073560.2:n.1636G>A		non-coding transcript variant
NC_000019.10:g.7647436G>A
NC_000019.9:g.7712322G>A
NG_016709.1:g.15332G>A
LRG_165:g.15332G>A

... more HGVS ... less HGVS

Protein change

G541S, G552S, G538S

Other names

Canonical SPDI

NC_000019.10:7647435:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

Allele frequency Help The frequency of the allele represented by this VCV record.

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008

Trans-Omics for Precision Medicine (TOPMed) 0.00021

Exome Aggregation Consortium (ExAC) 0.00024

Links

ClinGen: CA260033 OMIM: 601717.0007 dbSNP: rs61736587 VarSome

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
Gene	OMIM	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.
Familial hemophagocytic lymphohistiocytosis 5	Pathogenic/Likely pathogenic (8)	criteria provided, multiple submitters, no conflicts	Mar 21, 2024	RCV000024317.23
not provided	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Jan 28, 2024	RCV000519780.5
Autoinflammatory syndrome	Pathogenic (1)	criteria provided, single submitter	Apr 26, 2022	RCV002262571.3
Familial hemophagocytic lymphohistiocytosis	Pathogenic (1)	criteria provided, single submitter	Mar 27, 2023	RCV003226166.1
STXBP2-related disorder	Pathogenic (1)	no assertion criteria provided	Jun 28, 2024	RCV003398562.5

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.
Pathogenic (May 28, 2019)	criteria provided, single submitter (Mendelics Assertion Criteria 2017) Method: clinical testing	Familial hemophagocytic lymphohistiocytosis 5 Affected status: unknown Allele origin: unknown	Mendelics Accession: SCV001140968.1 First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020
Pathogenic (Jan 29, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial hemophagocytic lymphohistiocytosis 5 Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV003819765.2 First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024
Pathogenic (Mar 21, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial hemophagocytic lymphohistiocytosis 5 Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004205622.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024
Pathogenic (May 10, 2017)	criteria provided, single submitter (Blueprint Genetics Variant Classification Scheme) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Blueprint Genetics Accession: SCV000927257.1 First in ClinVar: Jul 24, 2019 Last updated: Jul 24, 2019 Comment: Patient analyzed with Primary Immunodeficiency Panel
Pathogenic (May 22, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial hemophagocytic lymphohistiocytosis 5 Affected status: yes Allele origin: germline	3billion Accession: SCV002521170.1 First in ClinVar: Jun 03, 2022 Last updated: Jun 03, 2022	Publications: PubMed (1) PubMed: 20798128 Comment: The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.023%). Functional studies provide strong evidence of the … (more) The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.023%). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 20798128). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.97; 3Cnet: 0.96). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic with strong evidence (ClinVar ID: VCV000030219). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less) Clinical Features: Hepatomegaly (present) , Splenomegaly (present) , Generalized hypotonia (present)
Pathogenic (Apr 26, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Autoinflammatory syndrome Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, The Hospital for Sick Children Accession: SCV002542993.1 First in ClinVar: Jul 09, 2022 Last updated: Jul 09, 2022
Likely pathogenic (Sep 03, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial hemophagocytic lymphohistiocytosis 5 (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Genetics and Molecular Pathology, SA Pathology Additional submitter: Shariant Australia, Australian Genomics Accession: SCV002761706.1 First in ClinVar: Dec 17, 2022 Last updated: Dec 17, 2022
Likely pathogenic (Dec 08, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial hemophagocytic lymphohistiocytosis 5 Affected status: yes Allele origin: germline	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center Accession: SCV003799015.2 First in ClinVar: Feb 13, 2023 Last updated: Mar 04, 2023	Comment: PS3, PM2, PP3
Pathogenic (Jan 31, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Familial hemophagocytic lymphohistiocytosis 5 Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000822990.6 First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024	Publications: PubMed (5) PubMed: 28492532‚ 20558610‚ 20798128‚ 20823128‚ 24194549 Comment: This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 541 of the STXBP2 protein (p.Gly541Ser). … (more) This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 541 of the STXBP2 protein (p.Gly541Ser). This variant is present in population databases (rs61736587, gnomAD 0.05%). This missense change has been observed in individuals with hemophagocytic lymphohistiocytosis type 5 (PMID: 20558610, 20798128, 20823128). ClinVar contains an entry for this variant (Variation ID: 30219). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt STXBP2 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects STXBP2 function (PMID: 20798128, 24194549). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Mar 27, 2023)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Familial hemophagocytic lymphohistiocytosis Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV003923007.1 First in ClinVar: May 13, 2023 Last updated: May 13, 2023	Publications: PubMed (2) PubMed: 22451424‚ 20798128 Comment: Variant summary: STXBP2 c.1621G>A (p.Gly541Ser) 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.1621G>A (p.Gly541Ser) 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 0.00023 in 248156 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in STXBP2 causing Familial Hemophagocytic Lymphohistiocytosis (0.00023 vs 0.0022), allowing no conclusion about variant significance. c.1621G>A has been reported in the literature as biallelic homozygous or compound heterozygous genotypes in multiple individuals affected with Familial Hemophagocytic Lymphohistiocytosis (example, Cetica_2010, Pagel_2012). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Cetica_2012). The most pronounced variant effect results in a defective protein and by defective cytotoxicity by T lymphocytes. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
Pathogenic (Jan 28, 2024)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000617868.4 First in ClinVar: Dec 19, 2017 Last updated: Sep 29, 2024	Comment: Published functional studies demonstrate the variant disrupts association of the protein with syntaxin 11, and functional assays show defective degranulation and cellular cytotoxicity (PMID: 20798128); … (more) Published functional studies demonstrate the variant disrupts association of the protein with syntaxin 11, and functional assays show defective degranulation and cellular cytotoxicity (PMID: 20798128); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20823128, 26320718, 23687090, 24194549, 32542393, 31589614, 35020838, 33162974, 20798128, 36706356) (less)
Pathogenic (Sep 01, 2010)	no assertion criteria provided Method: literature only	HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS, FAMILIAL, 5, WITH OR WITHOUT MICROVILLUS INCLUSION DISEASE Affected status: not provided Allele origin: germline	OMIM Accession: SCV000045608.4 First in ClinVar: Apr 04, 2013 Last updated: Jun 09, 2024	Publications: PubMed (2) PubMed: 20798128‚ 22451424 Comment on evidence: In a Caucasian girl from the United Kingdom with familial hemophagocytic lymphohistiocytosis-5 without microvillus inclusion disease (FHL5; 613101), Cetica et al. (2010) identified homozygosity for … (more) In a Caucasian girl from the United Kingdom with familial hemophagocytic lymphohistiocytosis-5 without microvillus inclusion disease (FHL5; 613101), Cetica et al. (2010) identified homozygosity for a 1621G-A transition in exon 18 of the STXBP2 gene, resulting in a gly541-to-ser (G541S) substitution at a highly conserved residue. The mutation was not found in 120 healthy Caucasian controls. Biochemical analysis revealed that G541S mutant disrupts association of STXBP2 with STX11 (605014). Granule release assay using the patient's lymphocytes showed minimal release in NK cells and completely absent release in CD3(+)CD8 cells; cytotoxic T-cell lymphocytes from the patient showed a reduced but not absent cell-killing capacity. She was still alive at 2.75 years of age after undergoing matched unrelated donor HSCT. In 3 unrelated children (A_376, A_032, and A_474) of European descent with FHL5, Pagel et al. (2012) identified compound heterozygous mutations in the STXBP2 gene. All 3 carried G541S on 1 allele and a putatively pathogenic variant on the other allele (a splice site mutation in exon 2, I104F, and L534P, respectively). Functional studies of the latter variants were not performed. The patients had onset of the disease in the first months of life; 1 died at age 7 months. One patient had chronic diarrhea due to enteropathy, and the other 2 had sensorineural hearing loss. Pagel et al. (2012) also reported a 19-year-old German girl (A_711) with later onset of FHL5 who was compound heterozygous for G541S and a splicing defect affecting exon 15 (c.1356+1G-A). Functional studies of the splice site mutation were not performed. The patient was diagnosed at age 13 years and underwent HSCT at age 17. She did not have enteropathy. (less)
Pathogenic (Jun 28, 2024)	no assertion criteria provided Method: clinical testing	STXBP2-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004119961.2 First in ClinVar: Nov 20, 2023 Last updated: Oct 08, 2024	Comment: The STXBP2 c.1621G>A variant is predicted to result in the amino acid substitution p.Gly541Ser. This variant was reported in the homozygous state in a patient … (more) The STXBP2 c.1621G>A variant is predicted to result in the amino acid substitution p.Gly541Ser. This variant was reported in the homozygous state in a patient with familial hemophagocytic lymphohistiocytosis (FHL) who lacked variants in the PRF1, UNC13D, and STX11 genes (Cetica et al. 2010. PubMed ID: 20798128). It has also been reported along with a second STXBP2 variant in other patients with FHL (Meeths et al. 2010. PubMed ID: 20558610; Rohr et al. 2010. PubMed ID: 20823128). Functional data in Cetica et al. suggest the p.Gly541Ser substitution affects binding of the STXBP2 protein to its effectors. This variant is reported in 0.047% of alleles in individuals of European (Non-Finnish) descent in gnomAD. It has been interpreted as pathogenic by multiple submitters to ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/30219). Taken together, this variant is interpreted as pathogenic. (less)
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Comment:

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.023%). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 20798128). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.97; 3Cnet: 0.96). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic with strong evidence (ClinVar ID: VCV000030219). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

Comment:

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 541 of the STXBP2 protein (p.Gly541Ser). This variant is present in population databases (rs61736587, gnomAD 0.05%). This missense change has been observed in individuals with hemophagocytic lymphohistiocytosis type 5 (PMID: 20558610, 20798128, 20823128). ClinVar contains an entry for this variant (Variation ID: 30219). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt STXBP2 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects STXBP2 function (PMID: 20798128, 24194549). For these reasons, this variant has been classified as Pathogenic.

Comment:

Variant summary: STXBP2 c.1621G>A (p.Gly541Ser) 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 0.00023 in 248156 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in STXBP2 causing Familial Hemophagocytic Lymphohistiocytosis (0.00023 vs 0.0022), allowing no conclusion about variant significance. c.1621G>A has been reported in the literature as biallelic homozygous or compound heterozygous genotypes in multiple individuals affected with Familial Hemophagocytic Lymphohistiocytosis (example, Cetica_2010, Pagel_2012). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Cetica_2012). The most pronounced variant effect results in a defective protein and by defective cytotoxicity by T lymphocytes. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

Comment:

Published functional studies demonstrate the variant disrupts association of the protein with syntaxin 11, and functional assays show defective degranulation and cellular cytotoxicity (PMID: 20798128); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20823128, 26320718, 23687090, 24194549, 32542393, 31589614, 35020838, 33162974, 20798128, 36706356)

Comment:

The STXBP2 c.1621G>A variant is predicted to result in the amino acid substitution p.Gly541Ser. This variant was reported in the homozygous state in a patient with familial hemophagocytic lymphohistiocytosis (FHL) who lacked variants in the PRF1, UNC13D, and STX11 genes (Cetica et al. 2010. PubMed ID: 20798128). It has also been reported along with a second STXBP2 variant in other patients with FHL (Meeths et al. 2010. PubMed ID: 20558610; Rohr et al. 2010. PubMed ID: 20823128). Functional data in Cetica et al. suggest the p.Gly541Ser substitution affects binding of the STXBP2 protein to its effectors. This variant is reported in 0.047% of alleles in individuals of European (Non-Finnish) descent in gnomAD. It has been interpreted as pathogenic by multiple submitters to ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/30219). Taken together, this variant is interpreted as pathogenic.

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:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Syntaxin binding mechanism and disease-causing mutations in Munc18-2.	Hackmann Y	Proceedings of the National Academy of Sciences of the United States of America	2013	PMID: 24194549
Distinct mutations in STXBP2 are associated with variable clinical presentations in patients with familial hemophagocytic lymphohistiocytosis type 5 (FHL5).	Pagel J	Blood	2012	PMID: 22451424
Atypical familial hemophagocytic lymphohistiocytosis due to mutations in UNC13D and STXBP2 overlaps with primary immunodeficiency diseases.	Rohr J	Haematologica	2010	PMID: 20823128
STXBP2 mutations in children with familial haemophagocytic lymphohistiocytosis type 5.	Cetica V	Journal of medical genetics	2010	PMID: 20798128
Spectrum of clinical presentations in familial hemophagocytic lymphohistiocytosis type 5 patients with mutations in STXBP2.	Meeths M	Blood	2010	PMID: 20558610

Text-mined citations for rs61736587 ...

These 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 13, 2024

ClinVar Genomic variation as it relates to human health

NM_006949.4(STXBP2):c.1621G>A (p.Gly541Ser)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs61736587 ...