rs794727970

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_003165.6(STXBP1):c.704G>A(p.Arg235Gln) variant causes a missense change involving the alteration of a 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R235G) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

STXBP1
NM_003165.6 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 8.15

Publications

13 publications found

Variant links:

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]

STXBP1 Gene-Disease associations (from GenCC):

developmental and epileptic encephalopathy, 4
Inheritance: AD, AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
genetic developmental and epileptic encephalopathy
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
atypical Rett syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
autosomal dominant non-syndromic intellectual disability
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Dravet syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
infantile spasms
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
undetermined early-onset epileptic encephalopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
autism spectrum disorder
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
intellectual disability
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

STXBP1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 18 ACMG points.

PM1

In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_003165.6

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr9-127666205-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 207455.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.992

PP5

Variant 9-127666206-G-A is Pathogenic according to our data. Variant chr9-127666206-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 199083.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STXBP1	NM_003165.6 link	c.704G>A	p.Arg235Gln	missense_variant	Exon 9 of 20	ENST00000373302.8	NP_003156.1	P61764-2
STXBP1	NM_001032221.6 link	c.704G>A	p.Arg235Gln	missense_variant	Exon 9 of 19	ENST00000373299.5	NP_001027392.1	P61764-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STXBP1	ENST00000373302.8 link	c.704G>A	p.Arg235Gln	missense_variant	Exon 9 of 20	1	NM_003165.6	ENSP00000362399.3		P61764-2
STXBP1	ENST00000373299.5 link	c.704G>A	p.Arg235Gln	missense_variant	Exon 9 of 19	1	NM_001032221.6	ENSP00000362396.2		P61764-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Developmental and epileptic encephalopathy, 4

Pathogenic:3

Nov 30, 2018

Institute of Human Genetics, University of Leipzig Medical Center

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 01, 2019

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 15, 2017

Genetic Services Laboratory, University of Chicago

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Pathogenic:2

May 26, 2015

Eurofins Ntd Llc (ga)

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 25, 2022

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Not observed in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; The majority of missense variants in this gene are considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 26865513, 25533962, 29056246, 28135719, 28191890, 29655203, 31474318, 34177756, 31175295, 31785789) -

Developmental and epileptic encephalopathy

Pathogenic:1

Oct 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 235 of the STXBP1 protein (p.Arg235Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with STXBP1-related encephalopathy and/or intellectual disability (PMID: 25533962, 26865513). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 199083). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt STXBP1 protein function with a positive predictive value of 95%. This variant disrupts the p.Arg235 amino acid residue in STXBP1. Other variant(s) that disrupt this residue have been observed in individuals with STXBP1-related conditions (PMID: 26865513, 29761117), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

Cerebellar vermis hypoplasia;C2677326:Developmental and epileptic encephalopathy, 4

Pathogenic:1

Feb 18, 2019

Dobyns Lab, Seattle Children's Research Institute

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

Congenital cerebellar hypoplasia

Pathogenic:1

University of Washington Center for Mendelian Genomics, University of Washington

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

Infantile epilepsy syndrome

Pathogenic:1

Nov 30, 2018

GenomeConnect - Simons Searchlight

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:provider interpretation

Submission from Simons Searchlight facilitated by GenomeConnect. Variant interpreted by the Simons Searchlight team most recently on 2018-11-30 and interpreted as Likely Pathogenic. Variant was initially reported by GTR ID of laboratory name 26957. The reporting laboratory might also submit to ClinVar. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.56

BayesDel_noAF

Pathogenic

0.57

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.49

.;T;.;T;.;T;D

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

1.0

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

D;.;D;D;D;D;D

M_CAP

Pathogenic

0.95

MetaRNN

Pathogenic

0.99

D;D;D;D;D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Uncertain

2.9

.;.;M;.;.;.;M

PhyloP100

8.1

PrimateAI

Pathogenic

0.84

PROVEAN

Uncertain

-3.8

.;.;D;.;.;.;D

REVEL

Pathogenic

0.96

Sift

Pathogenic

0.0

.;.;D;.;.;.;D

Sift4G

Pathogenic

0.0

.;.;D;.;.;.;D

Polyphen

1.0

.;.;D;.;.;.;D

Vest4

0.84, 0.84

MutPred

0.96

.;.;Loss of catalytic residue at R235 (P = 0.0323);Loss of catalytic residue at R235 (P = 0.0323);Loss of catalytic residue at R235 (P = 0.0323);.;Loss of catalytic residue at R235 (P = 0.0323);

MVP

0.97

MPC

2.6

ClinPred

1.0

GERP RS

5.7

Varity_R

0.93

gMVP

0.99

Mutation Taster

=2/98

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over