NM_001032221.6(STXBP1):c.1099C>T (p.Arg367Ter) AND Developmental and epileptic encephalopathy, 4

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Mar 5, 2022
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV001336021.8

Allele description [Variation Report for NM_001032221.6(STXBP1):c.1099C>T (p.Arg367Ter)]

NM_001032221.6(STXBP1):c.1099C>T (p.Arg367Ter)

Gene:

STXBP1:syntaxin binding protein 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

9q34.11

Genomic location:

Preferred name:

NM_001032221.6(STXBP1):c.1099C>T (p.Arg367Ter)

Other names:

p.R367*:CGA>TGA

HGVS:

NC_000009.12:g.127673250C>T
NG_016623.1:g.66044C>T
NM_001032221.6:c.1099C>TMANE SELECT
NM_001374306.2:c.1090C>T
NM_001374307.2:c.1057C>T
NM_001374308.2:c.1057C>T
NM_001374309.2:c.1057C>T
NM_001374310.2:c.1057C>T
NM_001374311.2:c.1057C>T
NM_001374312.2:c.1057C>T
NM_001374313.2:c.1099C>T
NM_001374314.1:c.1099C>T
NM_001374315.2:c.991C>T
NM_003165.6:c.1099C>T
NP_001027392.1:p.Arg367Ter
NP_001361235.1:p.Arg364Ter
NP_001361236.1:p.Arg353Ter
NP_001361237.1:p.Arg353Ter
NP_001361238.1:p.Arg353Ter
NP_001361239.1:p.Arg353Ter
NP_001361240.1:p.Arg353Ter
NP_001361241.1:p.Arg353Ter
NP_001361242.1:p.Arg367Ter
NP_001361243.1:p.Arg367Ter
NP_001361244.1:p.Arg331Ter
NP_003156.1:p.Arg367Ter
NC_000009.11:g.130435529C>T
NM_001032221.2:c.1099C>T
NM_003165.3:c.1099C>T
p.Arg367X

Protein change:

R331*

Links:

dbSNP: rs796053366

NCBI 1000 Genomes Browser:

rs796053366

Molecular consequence:

NM_001032221.6:c.1099C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001374306.2:c.1090C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001374307.2:c.1057C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001374308.2:c.1057C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001374309.2:c.1057C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001374310.2:c.1057C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001374311.2:c.1057C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001374312.2:c.1057C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001374313.2:c.1099C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001374314.1:c.1099C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001374315.2:c.991C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_003165.6:c.1099C>T - nonsense - [Sequence Ontology: SO:0001587]

Observations:

Condition(s)

Name:: Developmental and epileptic encephalopathy, 4 (DEE4)
Synonyms:: Early infantile epileptic encephalopathy 4; STXBP1-Related Epileptic Encephalopathy
Identifiers:: MONDO: MONDO:0012812; MedGen: C2677326; Orphanet: 1934; Orphanet: 33069; OMIM: 612164

Recent activity

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Astarte castanea cytochrome oxidase 1 (COI) gene, partial cds; mitochondrial gene for mitochondrial product
gi|18026505|gb|AF120662.1|

Nucleotide
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Sepia officinalis isolate SOIM1H cytochrome c oxidase subunit I gene, partial cds; mitochondrial
gi|1761173804|gb|MN069250.1|

Nucleotide
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Sepia officinalis isolate SOPP1H cytochrome c oxidase subunit I gene, partial cds; mitochondrial
gi|1761173802|gb|MN069249.1|

Nucleotide
TET16 tetraspanin [Arabidopsis thaliana]
TET16 tetraspanin [Arabidopsis thaliana]
Gene ID:838432

Gene

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001529296	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 1, 2018)	de novo	clinical testing	PubMed (4) [See all records that cite these PMIDs] 25533962, 28135719, 27159321, 25741868
SCV002107137	DASA	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 5, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 26918652, 28135719, 27159321, 25741868
SCV002820125	Neuberg Centre For Genomic Medicine, NCGM	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001529296

Baylor Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Dec 1, 2018)

de novo

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

SCV002107137

DASA

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Mar 5, 2022)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

SCV002820125

Neuberg Centre For Genomic Medicine, NCGM

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	de novo	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Large-scale discovery of novel genetic causes of developmental disorders.

Deciphering Developmental Disorders Study..

Nature. 2015 Mar 12;519(7542):223-8. doi: 10.1038/nature14135. Epub 2014 Dec 24.

PubMed [citation]

PMID:: 25533962
PMCID:: PMC5955210

Mislocalization of syntaxin-1 and impaired neurite growth observed in a human iPSC model for STXBP1-related epileptic encephalopathy.

Yamashita S, Chiyonobu T, Yoshida M, Maeda H, Zuiki M, Kidowaki S, Isoda K, Morimoto M, Kato M, Saitsu H, Matsumoto N, Nakahata T, Saito MK, Hosoi H.

Epilepsia. 2016 Apr;57(4):e81-6. doi: 10.1111/epi.13338. Epub 2016 Feb 25.

PubMed [citation]

PMID:: 26918652

See all PubMed Citations (5)

Details of each submission

From Baylor Genetics, SCV001529296.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as disease-causing [PMID 25533962, 28135719, 27159321]

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	de novo	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From DASA, SCV002107137.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (4)

Description

The c.1099C>T;p.(Arg367*) variant creates a premature translational stop signal in the STXBP1 gene. It is expected to result in an absent or disrupted protein product - PVS1. Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 26918652) - PS3_supporting. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 207429; PMID: 28135719; PMID: 27159321; PMID: 26918652) - PS4. This variant is not present in population databases (rs796053366- gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. The variant was assumed de novo, but without confirmation of paternity and maternity (PMID: 27159321; 26918652) - PM6. In summary, the currently available evidence indicates that the variant is pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

From Neuberg Centre For Genomic Medicine, NCGM, SCV002820125.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

The stop gained p.R367* in STXBP1 (NM_003165.6) has been previously identified de novo in 2 individuals with features of STXBP1 encephalopathy (Stamberger 2016, Yamashita 2016). Heterozygous loss-of-function variants in the STXBP1 gene are causative for STXBP1 encephalopathy. The variant has been reported to ClinVar as Pathogenic. The p.R367* variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This variant is predicted to cause loss of normal protein function through protein truncation. The p.R367* variant is a loss of function variant in the gene STXBP1, which is intolerant of Loss of Function variants, as indicated by the presence of existing pathogenic loss of function variant NP_003156.1:p.M1Lfs*604 and 119 others. For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Nov 3, 2024

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