rs121918318

Variant names:

• chr9-127663314-G-A
• rs121918318
• NM_003165.6:c.539G>A

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM2 PP3_Strong PP5_Moderate

The NM_003165.6(STXBP1):​c.539G>A​(p.Cys180Tyr) 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 (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: STXBP1 NM_003165.6 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 9.91
• Publications: 14 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 10 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 7 uncertain in NM_003165.6
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.976
• PP5: Variant 9-127663314-G-A is Pathogenic according to our data. Variant chr9-127663314-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 6727.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003165.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STXBP1	NM_003165.6	MANE Plus Clinical	c.539G>A	p.Cys180Tyr	missense	Exon 7 of 20	NP_003156.1
	STXBP1	NM_001032221.6	MANE Select	c.539G>A	p.Cys180Tyr	missense	Exon 7 of 19	NP_001027392.1
	STXBP1	NM_001374306.2		c.530G>A	p.Cys177Tyr	missense	Exon 7 of 19	NP_001361235.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STXBP1	ENST00000373302.8	TSL:1 MANE Plus Clinical	c.539G>A	p.Cys180Tyr	missense	Exon 7 of 20	ENSP00000362399.3
	STXBP1	ENST00000373299.5	TSL:1 MANE Select	c.539G>A	p.Cys180Tyr	missense	Exon 7 of 19	ENSP00000362396.2
	STXBP1	ENST00000494254.4	TSL:5	c.539G>A	p.Cys180Tyr	missense	Exon 7 of 19	ENSP00000485397.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Sep 30, 2016

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.C180Y pathogenic mutation (also known as c.539G>A), located in coding exon 7 of the STXBP1 gene, results from a G to A substitution at nucleotide position 539. The cysteine at codon 180 is replaced by tyrosine, an amino acid with highly dissimilar properties. This mutation has been reported as a de novo occurrence in an individual with epileptic encephalopathy (Saitsu H et al. Nat. Genet., 2008 Jun;40:782-8). Functional studies indicate that this mutation impairs membrane vesicle fusion (Martin S et al. Cell Rep, 2014 Oct;9:206-18). Based on internal structural analysis, this alteration is anticipated to result in a significant decrease in structural stability (Colbert KN et al. Proc. Natl. Acad. Sci. U.S.A., 2013 Jul;110:12637-42). In addition, a different alteration located at the same position, p.C180R (c.538T>C) was detected as a de novo occurrence in a male individual with Rett-like syndrome (Lopes, et al. J. Med. Genet. 2016 Mar;53(3):190-9). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

Developmental and epileptic encephalopathy, 4 Pathogenic:1

Jun 01, 2008

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.48	T
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.72	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.74	D
MutationAssessor	Pathogenic	3.1	M
PhyloP100		9.9
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-10	D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.95
MutPred		0.85		Loss of catalytic residue at T182 (P = 0.1224)
MVP		0.93
MPC		3.1
ClinPred		1.0	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.99
gMVP		0.98
Mutation Taster		=2/98	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: rs121918318; hg19: chr9-130425593;