9-127682510-G-C

Variant names:

• chr9-127682510-G-C
• rs796053374
• NM_003165.6:c.1652G>C

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Moderate

The NM_003165.6(STXBP1):​c.1652G>C​(p.Arg551Pro) 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R551H) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: STXBP1 NM_003165.6 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.86
• Publications: 10 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 12 ACMG points.

• PM1: In a hotspot region, there are 12 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 12 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 chr9-127682510-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 566474.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.963
• PP5: Variant 9-127682510-G-C is Pathogenic according to our data. Variant chr9-127682510-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 207441.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STXBP1	NM_003165.6	c.1652G>C	p.Arg551Pro	missense_variant	Exon 18 of 20	ENST00000373302.8	NP_003156.1
STXBP1	NM_001032221.6	c.1652G>C	p.Arg551Pro	missense_variant	Exon 18 of 19	ENST00000373299.5	NP_001027392.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STXBP1	ENST00000373302.8	c.1652G>C	p.Arg551Pro	missense_variant	Exon 18 of 20	1	NM_003165.6	ENSP00000362399.3
STXBP1	ENST00000373299.5	c.1652G>C	p.Arg551Pro	missense_variant	Exon 18 of 19	1	NM_001032221.6	ENSP00000362396.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

May 25, 2017

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Arg551Pro (CGC>CCC): c.1652 G>C in exon 18 of the STXBP1 gene (NM_003165.2)The novel R551P missense change in the STXBP1 gene has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. However, a different amino acid substitution at the same codon, R551C, was previously reported as a de novo change in a patient with an autism spectrum disorder, although no additional information was provided regarding the patient's phenotype (Neale et al., 2012). The R551C variant subsequently has been reported as a de novo pathogenic variant in a child with infantile epileptic encephalopathy, intellectual disability, and ataxia (Weckhuysen et al., 2013). The R551P variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R551P variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. R551P alters a highly conserved position in the protein, and other missense variants have been reported in this region of the protein in the Human Gene Mutation Database in association with epilepsy (Stenson et al., 2014). Additionally, in silico analysis predicts this variant is probably damaging to the protein structure/function. The variant is found in EPILEPSY panel(s). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.40
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.43	.;T;.;T;.;T;D;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;D
M_CAP	Pathogenic	0.82	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.83	D
MutationAssessor	Pathogenic	3.2	.;.;M;.;.;.;M;.
PhyloP100		9.9
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-6.8	.;.;D;.;.;.;D;.
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	.;.;D;.;.;.;D;.
Sift4G	Pathogenic	0.0010	.;.;D;.;.;.;D;D
Polyphen		1.0	.;.;D;.;.;.;D;.
Vest4		0.98, 0.98
MutPred		0.81		.;.;Loss of methylation at R551 (P = 0.0985);Loss of methylation at R551 (P = 0.0985);Loss of methylation at R551 (P = 0.0985);.;Loss of methylation at R551 (P = 0.0985);.;
MVP		0.94
MPC		2.8
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.99
gMVP		1.0
Mutation Taster		=0/100	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: rs796053374; hg19: chr9-130444789;