Submissions for variant NM_001032221.6(STXBP1):c.1003C>T (p.Pro335Ser)

dbSNP: rs1085307916

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000489992	SCV000577661	likely pathogenic	not provided	2015-07-30	criteria provided, single submitter	clinical testing	The P335S variant has not been published as a pathogenic variant, nor has it been reported as a benign polymorphism to our knowledge. However, a missense variant at the same residue (P335L) has been reported in the Human Gene Mutation Database in association with infantile spasms (Stenson et al., 2014). The P335S variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The P335S 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. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, this variant is a strong candidate for a pathogenic variant, however the possibility that it is a benign variant cannot be excluded.
Diagnostic Genetics, Severance Hospital, Yonsei University College of Medicine	RCV002466257	SCV002761335	likely pathogenic	Developmental and epileptic encephalopathy, 4	2022-02-03	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV003753124	SCV004551642	pathogenic	Early infantile epileptic encephalopathy with suppression bursts	2023-03-01	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 335 of the STXBP1 protein (p.Pro335Ser). This missense change has been observed in individual(s) with clinical features of STXBP1-related conditions and/or epilepsy and neurodevelopmental disorders (PMID: 29655203; Invitae). In at least one individual the variant was observed to be de novo. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Pro335 amino acid residue in STXBP1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23934111, 29186148, 30174244). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 427039).