9-127675909-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM2PM5PP2PP3_StrongPP5_Very_Strong

The NM_001032221.6(STXBP1):c.1216C>T(p.Arg406Cys) 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. 13/21 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. R406H) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

STXBP1
NM_001032221.6 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:11

Conservation

PhyloP100: 7.91

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 17 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr9-127675910-G-A is described in Lovd as [Pathogenic].

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: 5.8379 (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, 0.987

PP5

Variant 9-127675909-C-T is Pathogenic according to our data. Variant chr9-127675909-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 207431.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-127675909-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STXBP1	NM_003165.6 link	c.1216C>T	p.Arg406Cys	missense_variant	Exon 14 of 20	ENST00000373302.8	NP_003156.1	P61764-2
STXBP1	NM_001032221.6 link	c.1216C>T	p.Arg406Cys	missense_variant	Exon 14 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.1216C>T	p.Arg406Cys	missense_variant	Exon 14 of 20	1	NM_003165.6	ENSP00000362399.3		P61764-2
STXBP1	ENST00000373299.5 link	c.1216C>T	p.Arg406Cys	missense_variant	Exon 14 of 19	1	NM_001032221.6	ENSP00000362396.2		P61764-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Developmental and epileptic encephalopathy, 4

Pathogenic:5

Nov 20, 2019

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -

Nov 17, 2021

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS2, PM2, PS4 -

Jan 09, 2020

Pediatric Department, Xiangya Hospital, Central South University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 08, 2002

Center of Excellence for Medical Genomics, Chulalongkorn University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Jun 10, 2022

DASA

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1216C>T;p.(Arg406Cys) missense change has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID: 207431; PMID: 28947817; 28387369; 27171548; 26648591) - PS4. This variant is not present in population databases:rs796053367, gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. Pathogenic missense variant in this residue have been reported and classified as Pathogenic by ACMG criteria (Clinvar ID: 279904 - c.1217G>A;p.(Arg406His); Clinvar ID: 419223 - c.1217G>T (p.Arg406Leu)) - PM5. The variant was assumed de novo, but without confirmation of paternity and maternity (PMID: 28387369; 27171548; 26648591)PM6. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is Pathogenic -

not provided

Pathogenic:2

Jul 01, 2019

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 11, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are often considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 35007884, 28947817, 29390993, 26648591, 28387369, 27171548, 31344879, 31487502, 27864847, 32005694, 32139178, 28191889, 31175295, 33004838, 35851549, 31440721, 34145886, 35190816, 29190809) -

Inborn genetic diseases

Pathogenic:1

Nov 03, 2023

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1216C>T (p.R406C) alteration is located in coding exon 14 of the STXBP1 gene. This alteration results from a C to T substitution at nucleotide position 1216, causing the arginine (R) at amino acid position 406 to be replaced by a cysteine (C). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been reported as a de novo finding in an individual with a history of seizures, profound intellectual disability (ID), ocular wobble, limb spasticity, progressive microcephaly with brain atrophy, and percutaneous endoscopic gastrostomy (Allen, 2015). The c.1216C>T (p.R406C) variant has also been reported as a pathogenic de novo finding in a 2 month old Chinese male with epilepsy and global developmental delay (Zou, 2021). Another alteration at the same codon, c.1217G>A (p.R406H), is a well known pathogenic variant in the STXBP1 gene and has been reported as a de novo finding in several unrelated affected individuals with early onset seizures, severe to profound ID, specific abnormal EEG findings, infantile spasms, spastic quadraplegia, limb hypertonia, ataxic gait, and autistic features (Saitsu, 2010; Mignot, 2011; Epi4k, 2013; Romaniello, 2015; Stamberger, 2016). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

Early infantile epileptic encephalopathy with suppression bursts

Pathogenic:1

Feb 25, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine with cysteine at codon 406 of the STXBP1 protein (p.Arg406Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. For these reasons, this variant has been classified as Pathogenic. A different missense substitution at this codon (p.Arg406His) has been determined to be pathogenic (PMID: 20887364, 21762454, 23934111). This suggests that the arginine residue is critical for STXBP1 protein function and that other missense substitutions at this position may also be pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been reported to be de novo in several individuals affected with early-onset epileptic encephalopathy (PMID: 26648591, 28387369) and several individuals affected with Rett-like syndrome (PMID: 28947817, 27171548). ClinVar contains an entry for this variant (Variation ID: 207431). This variant is not present in population databases (ExAC no frequency). -

Epileptic encephalopathy

Pathogenic:1

Nov 16, 2016

Neurogenetics Laboratory - MEYER, AOU Meyer

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Infantile epilepsy syndrome

Pathogenic:1

Jan 27, 2017

GenomeConnect - Simons Searchlight

Significance: 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 2017-01-27 and interpreted as Pathogenic. Variant was initially reported on 2013-05-06 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

0.99

BayesDel_addAF

Pathogenic

0.49

BayesDel_noAF

Pathogenic

0.47

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.50

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

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.94

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Pathogenic

1.0

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

M_CAP

Pathogenic

0.75

MetaRNN

Pathogenic

0.99

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

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

3.3

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

PrimateAI

Pathogenic

0.92

PROVEAN

Pathogenic

-7.9

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

REVEL

Pathogenic

0.93

Sift

Pathogenic

0.0

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

Sift4G

Pathogenic

0.0

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

Polyphen

1.0

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

Vest4

0.96, 0.96

MutPred

0.89

.;.;Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);.;Loss of sheet (P = 0.1158);

MVP

0.97

MPC

2.7

ClinPred

1.0

GERP RS

5.6

Varity_R

0.94

gMVP

0.98

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over