rs796053366

Positions:

• chr9-127673250-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_003165.6(STXBP1):​c.1099C>T​(p.Arg367Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: STXBP1 NM_003165.6 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 1.62

Genes affected

STXBP1 (HGNC:11444): (syntaxin binding protein 1) This gene encodes a syntaxin-binding protein. The encoded protein appears to play a role in release of neurotransmitters via regulation of syntaxin, a transmembrane attachment protein receptor. Mutations in this gene have been associated with infantile epileptic encephalopathy-4. Alternatively spliced transcript variants have been described. [provided by RefSeq, Feb 2010]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-127673250-C-T is Pathogenic according to our data. Variant chr9-127673250-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 207429.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-127673250-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
STXBP1	NM_003165.6	c.1099C>T	p.Arg367Ter	stop_gained	13/20	ENST00000373302.8	NP_003156.1
STXBP1	NM_001032221.6	c.1099C>T	p.Arg367Ter	stop_gained	13/19	ENST00000373299.5	NP_001027392.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
STXBP1	ENST00000373302.8	c.1099C>T	p.Arg367Ter	stop_gained	13/20	1	NM_003165.6	ENSP00000362399	P3
STXBP1	ENST00000373299.5	c.1099C>T	p.Arg367Ter	stop_gained	13/19	1	NM_001032221.6	ENSP00000362396	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Developmental and epileptic encephalopathy, 4 Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	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. -
Pathogenic, criteria provided, single submitter	clinical testing	DASA	Mar 05, 2022	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Dec 01, 2018	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] -

Early infantile epileptic encephalopathy with suppression bursts Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 06, 2016	The p.Arg367X variant in STXBP1 has been previously identified de novo in 2 indi viduals with features of STXBP1 encephalopathy (Stamberger 2016, Yamashita 2016) , and was absent from large population studies. This nonsense variant leads to a premature termination codon at position 367, which is predicted to lead to a tr uncated or absent protein. Heterozygous loss-of-function variants in the STXBP1 gene are causative for STXBP1 encephalopathy. In summary, this variant meets our criteria to be classified as pathogenic for STXBP1 encephalopathy in an autosom al dominant manner based upon its predicted impact to the protein, de novo occur rences in affected individuals and absence in the general population. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 25, 2023	This sequence change creates a premature translational stop signal (p.Arg367*) in the STXBP1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in STXBP1 are known to be pathogenic (PMID: 20887364, 26384463). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Ohtahara syndrome or early infantile epileptic encephalopathy (PMID: 26918652, 27159321). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 207429). For these reasons, this variant has been classified as Pathogenic. -

Epileptic encephalopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Neurogenetics Laboratory - MEYER, AOU Meyer

Nov 16, 2016

- -

Cerebellar ataxia;C0040822:Tremor;C2237142:Moderate global developmental delay Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University Hospital Muenster

Dec 04, 2021

ACMG categories: PVS1,PS2,PM2,PP3,PP5 -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jun 20, 2022

Nonsense variant predicted to result in protein truncation or nonsense-mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26865513, 23593750, 28944233, 25533962, 27159321, 26918652, 29538625, 30187003, 28135719, 31344879, 31785789, 33726816, 31440721, 28191890, 29655203, 36480001, 33057194, 36939041, 36801247, 36475376, 35982159) -

Infantile epilepsy syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

provider interpretation

GenomeConnect - Simons Searchlight

Nov 10, 2017

Submission from Simons Searchlight facilitated by GenomeConnect. Variant interpreted by the Simons Searchlight team most recently on 2017-11-10 and interpreted as Pathogenic. Variant was initially reported on 2013-01-14 by GTR ID of laboratory name 26957. The reporting laboratory might also submit to ClinVar. -

Intellectual disability Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Diagnostic Laboratory, Strasbourg University Hospital

Sep 10, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.66
CADD	Pathogenic	38
DANN	Uncertain	1.0
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.98	D
MutationTaster	Benign	1.0	A;A
Vest4		0.96
GERP RS		5.5

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs796053366; hg19: chr9-130435529;