NM_001032221.6(STXBP1):c.754A>G (p.Met252Val) AND Early infantile epileptic encephalopathy with suppression bursts

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Nov 4, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV003588952.2

Allele description [Variation Report for NM_001032221.6(STXBP1):c.754A>G (p.Met252Val)]

NM_001032221.6(STXBP1):c.754A>G (p.Met252Val)

Gene:

STXBP1:syntaxin binding protein 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

9q34.11

Genomic location:

Preferred name:

NM_001032221.6(STXBP1):c.754A>G (p.Met252Val)

HGVS:

NC_000009.12:g.127666256A>G
NG_016623.1:g.59050A>G
NG_016623.2:g.59346A>G
NM_001032221.6:c.754A>GMANE SELECT
NM_001374306.2:c.745A>G
NM_001374307.2:c.712A>G
NM_001374308.2:c.712A>G
NM_001374309.2:c.712A>G
NM_001374310.2:c.712A>G
NM_001374311.2:c.712A>G
NM_001374312.2:c.712A>G
NM_001374313.2:c.754A>G
NM_001374314.1:c.754A>G
NM_001374315.2:c.754A>G
NM_003165.6:c.754A>G
NP_001027392.1:p.Met252Val
NP_001361235.1:p.Met249Val
NP_001361236.1:p.Met238Val
NP_001361237.1:p.Met238Val
NP_001361238.1:p.Met238Val
NP_001361239.1:p.Met238Val
NP_001361240.1:p.Met238Val
NP_001361241.1:p.Met238Val
NP_001361242.1:p.Met252Val
NP_001361243.1:p.Met252Val
NP_001361244.1:p.Met252Val
NP_003156.1:p.Met252Val
NC_000009.11:g.130428535A>G

Protein change:

M238V

Molecular consequence:

NM_001032221.6:c.754A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001374306.2:c.745A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001374307.2:c.712A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001374308.2:c.712A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001374309.2:c.712A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001374310.2:c.712A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001374311.2:c.712A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001374312.2:c.712A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001374313.2:c.754A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001374314.1:c.754A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001374315.2:c.754A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_003165.6:c.754A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Early infantile epileptic encephalopathy with suppression bursts (EIEE)
Synonyms:: Early infantile epileptic encephalopathy; Ohtahara syndrome; Developmental and epileptic encephalopathy
Identifiers:: MONDO: MONDO:0100062; MedGen: C0393706; Orphanet: 1934; OMIM: PS308350

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004245964	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Nov 4, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 28771251, 29264391, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004245964

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Nov 4, 2023)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Improved diagnostic yield compared with targeted gene sequencing panels suggests a role for whole-genome sequencing as a first-tier genetic test.

Lionel AC, Costain G, Monfared N, Walker S, Reuter MS, Hosseini SM, Thiruvahindrapuram B, Merico D, Jobling R, Nalpathamkalam T, Pellecchia G, Sung WWL, Wang Z, Bikangaga P, Boelman C, Carter MT, Cordeiro D, Cytrynbaum C, Dell SD, Dhir P, Dowling JJ, Heon E, et al.

Genet Med. 2018 Apr;20(4):435-443. doi: 10.1038/gim.2017.119. Epub 2017 Aug 3.

PubMed [citation]

PMID:: 28771251
PMCID:: PMC5895460

Germline and somatic mutations in STXBP1 with diverse neurodevelopmental phenotypes.

Uddin M, Woodbury-Smith M, Chan A, Brunga L, Lamoureux S, Pellecchia G, Yuen RKC, Faheem M, Stavropoulos DJ, Drake J, Hahn CD, Hawkins C, Shlien A, Marshall CR, Turner LA, Minassian BA, Scherer SW, Boelman C.

Neurol Genet. 2017 Dec;3(6):e199. doi: 10.1212/NXG.0000000000000199.

PubMed [citation]

PMID:: 29264391
PMCID:: PMC5735305

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004245964.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 252 of the STXBP1 protein (p.Met252Val). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with STXBP1-related conditions. 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 with a positive predictive value of 95%. This variant disrupts the p.Met252 amino acid residue in STXBP1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 28771251, 29264391). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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