rs121918321

chr9-127675855-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.1162C>T(p.Arg388Ter) variant causes a stop gained change. 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 (★★). Synonymous variant affecting the same amino acid position (i.e. R388R) has been classified as Likely benign. 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:8 O:1
• Conservation: PhyloP100: 4.20

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 9-127675855-C-T is Pathogenic according to our data. Variant chr9-127675855-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 6730.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-127675855-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STXBP1	NM_003165.6	c.1162C>T	p.Arg388Ter	stop_gained	14/20	ENST00000373302.8
STXBP1	NM_001032221.6	c.1162C>T	p.Arg388Ter	stop_gained	14/19	ENST00000373299.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STXBP1	ENST00000373302.8	c.1162C>T	p.Arg388Ter	stop_gained	14/20	1	NM_003165.6	P3
STXBP1	ENST00000373299.5	c.1162C>T	p.Arg388Ter	stop_gained	14/19	1	NM_001032221.6	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Developmental and epileptic encephalopathy, 4 Pathogenic:4 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Apr 19, 2024	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 2009	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Dec 05, 2019	This variant was identified as de novo (maternity and paternity confirmed). -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	May 11, 2022	- -
not provided, no classification provided	literature only	GeneReviews	-	- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 10, 2018

- -

Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Apr 16, 2022

This sequence change creates a premature translational stop signal (p.Arg388*) 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 (PMID: 19557857, 26514728, 27184330). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 6730). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

May 29, 2018

The R388X pathogenic nonsense variant in the STXBP1 gene has been reported previously occurring de novo with confirmed parentage in a patient with intellectual disability with nonsyndromic epilepsy (Hamdan et al., 2009). It was subsequently reported as a de novo pathogenic variant in a patient with ataxia-tremor-retardation syndrome who did not have a history of seizures (Gburek-Augustat et al., 2016). This pathogenic variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The R388X variant is not observed in large population cohorts (Lek et al., 2016). Therefore, R388X is interpreted to be a pathogenic variant and its presence is consistent with the diagnosis of a STXBP1-related disorder in this individual. -

Infantile epilepsy syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

provider interpretation

GenomeConnect - Simons Searchlight

Apr 01, 2019

Submission from Simons Searchlight facilitated by GenomeConnect. Variant interpreted by the Simons Searchlight team most recently on 2019-04-01 and interpreted as Pathogenic. Variant was initially reported on 2018-10-17 by GTR ID of laboratory name 61756. The reporting laboratory might also submit to ClinVar. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.60
Cadd	Pathogenic	36
Dann	Uncertain	1.0
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.87	D
MutationTaster	Benign	1.0	A;A
Vest4		0.95
GERP RS		1.8

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: rs121918321; hg19: chr9-130438134; COSMIC: COSV104681331; COSMIC: COSV104681331;