rs587784453

Variant names:

• chr9-127666236-A-G
• rs587784453
• NM_003165.6:c.734A>G

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_003165.6(STXBP1):​c.734A>G​(p.His245Arg) 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. 13/22 in silico tools predict a damaging 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. H245N) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: STXBP1 NM_003165.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 9.32
• Publications: 3 publications found

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

ACMG classification

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

• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 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 chr9-127666235-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 1298373.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991
• PP5: Variant 9-127666236-A-G is Pathogenic according to our data. Variant chr9-127666236-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 160070.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	c.734A>G	p.His245Arg	missense_variant	Exon 9 of 20	ENST00000373302.8	NP_003156.1
STXBP1	NM_001032221.6	c.734A>G	p.His245Arg	missense_variant	Exon 9 of 19	ENST00000373299.5	NP_001027392.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STXBP1	ENST00000373302.8	c.734A>G	p.His245Arg	missense_variant	Exon 9 of 20	1	NM_003165.6	ENSP00000362399.3
STXBP1	ENST00000373299.5	c.734A>G	p.His245Arg	missense_variant	Exon 9 of 19	1	NM_001032221.6	ENSP00000362396.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Developmental and epileptic encephalopathy, 4 Pathogenic:2

Nov 11, 2022

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 17, 2013

Genetic Services Laboratory, University of Chicago

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

DNA sequence analysis of the STXBP1 gene demonstrated a sequence change, c.734A>G, in exon 9 that results in an amino acid change, p.His245Arg. This sequence change does not appear to have been previously described in patients with STXBP1-related disorders and has also not been described as a known benign sequence change in the STXBP1 gene. The p.His245Arg change affects a highly conserved amino acid residue located in a domain of the STXBP1 protein that is known to be functional. The p.His245Arg substitution appears to be deleterious using the SIFT in-silico prediction tool, and the PolyPhen-2 software predicts a probably damaging effect of the p.His245Arg substitution on the function of the STXBP1 protein. This variant was also identified to be present in the de novo state in the patient tested in our laboratory. -

Developmental and epileptic encephalopathy Pathogenic:1

Apr 24, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 STXBP1 protein function. This variant disrupts the p.His245 amino acid residue in STXBP1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 26514728). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 160070). This missense change has been observed in individual(s) with epileptic encephalopathy and intellectual disability (PMID: 25693842; Invitae). In at least one individual the variant was observed to be de novo. This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 245 of the STXBP1 protein (p.His245Arg). This variant is not present in population databases (gnomAD no frequency). -

Infantile epilepsy syndrome Pathogenic:1

Dec 18, 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 2018-12-18 and interpreted as Likely Pathogenic. Variant was initially reported on 2017-10-26 by GTR ID of laboratory name 500031. The reporting laboratory might also submit to ClinVar. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.50	.;D;.;D;.;D;D
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	D;.;D;D;D;D;D
M_CAP	Pathogenic	0.66	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.83	D
MutationAssessor	Pathogenic	3.2	.;.;M;.;.;.;M
PhyloP100		9.3
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-7.6	.;.;D;.;.;.;D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	.;.;D;.;.;.;D
Sift4G	Pathogenic	0.0	.;.;D;.;.;.;D
Polyphen		1.0	.;.;D;.;.;.;D
Vest4		0.94, 0.94
MutPred		0.91		.;.;Loss of catalytic residue at L247 (P = 0.0694);Loss of catalytic residue at L247 (P = 0.0694);Loss of catalytic residue at L247 (P = 0.0694);.;Loss of catalytic residue at L247 (P = 0.0694);
MVP		0.98
MPC		1.5
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.93
gMVP		1.0
Mutation Taster		=1/99	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs587784453; hg19: chr9-130428515;