NM_003165.6:c.704G>A

Variant names:

• chr9-127666206-G-A
• rs794727970
• NM_003165.6:c.704G>A

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM2 PP2 PP3_Strong PP5_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 (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: STXBP1 NM_003165.6 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 8.15

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 15 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the STXBP1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 106 curated pathogenic missense variants (we use a threshold of 10). The gene has 79 curated benign missense variants. Gene score misZ: 4.263 (above the threshold of 3.09). Trascript score misZ: 5.8329 (above the threshold of 3.09). GenCC associations: The gene is linked to intellectual disability, autosomal dominant non-syndromic intellectual disability, Dravet syndrome, undetermined early-onset epileptic encephalopathy, autism spectrum disorder, developmental and epileptic encephalopathy, West syndrome, atypical Rett syndrome, developmental and epileptic encephalopathy, 4.
• 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 id is 199083.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-127666206-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STXBP1	NM_003165.6	c.704G>A	p.Arg235Gln	missense_variant	Exon 9 of 20	ENST00000373302.8	NP_003156.1
STXBP1	NM_001032221.6	c.704G>A	p.Arg235Gln	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.704G>A	p.Arg235Gln	missense_variant	Exon 9 of 20	1	NM_003165.6	ENSP00000362399.3
STXBP1	ENST00000373299.5	c.704G>A	p.Arg235Gln	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

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

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) -

Early infantile epileptic encephalopathy with suppression bursts 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	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	33
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	D
LIST_S2	Pathogenic	0.99	D;.;D;D;D;D;D
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.9	.;.;M;.;.;.;M
PrimateAI	Pathogenic	0.84	D
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	D
GERP RS		5.7
Varity_R		0.93
gMVP		0.99

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

LitVar

Other links and lift over

dbSNP: rs794727970; hg19: chr9-130428485; COSMIC: COSV64812069; COSMIC: COSV64812069;