Submissions for variant NM_001032221.6(STXBP1):c.1004C>T (p.Pro335Leu)

dbSNP: rs398123695

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000080077	SCV000111972	uncertain significance	not provided	2013-10-04	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001795096	SCV002034862	pathogenic	STXBP1-related neurodevelopmental disorder	2021-09-24	criteria provided, single submitter	clinical testing	The STXBP1 c.1004C>T (p.Pro335Leu) variant is a missense variant that has been reported in a de novo heterozygous state in two individuals with early infantile epileptic encephalopathy and one individual with neurodevelopmental disorder (Epi4K Consortium 2013; Zhu et al. 2017; Aldinger et al. 2019). This variant is not found in version 2.1.1 or version 3.1.1 of the Genome Aggregation Database despite its location in a region of good sequence coverage, which suggests the variant is rare. The Pro335 residue was demonstrated to function as a hinge point in the alpha-helical region and was shown to be important for binding with other proteins (Hu et al. 2011; Han et al. 2014). The residue also lies within domain 3a, which is noted to be critical for vesicular priming (Lanoue et al. 2019). A C. elegans knock-in model showed that worms carrying the p.Pro335Leu-equivalent variant exhibited impairments to locomotion and heat shock paralysis and an increase in neurotransmitter release (Guiberson et al. 2018). Another C. elegans model showed that, while transgenic expression of the p.Pro335Leu-equivalent variant did not result in impaired locomotion, the worms displayed irregular pharyngeal contractions, strong seizure phenotype, and reduced protein expression when compared to wildtype and controls (Zhu et al. 2020). Guiberson et al. (2018) also demonstrated increased neuronal activity in primary neurons from p.Pro335Leu variant conditional knock-out mice. Based on the available evidence, the p.Pro335Leu variant is classified as pathogenic for STXBP1-related neurodevelopmental disorder.
Invitae	RCV002514407	SCV003441307	pathogenic	Early infantile epileptic encephalopathy with suppression bursts	2022-04-25	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 335 of the STXBP1 protein (p.Pro335Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with STXBP1-related conditions (PMID: 23934111, 29186148, 30174244). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 94116). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects STXBP1 function (PMID: 30540253, 32112430).
Dobyns Lab, Seattle Children's Research Institute	RCV000779645	SCV000916322	likely pathogenic	Developmental and epileptic encephalopathy, 4; West syndrome; Cerebellar vermis hypoplasia	2019-02-18	no assertion criteria provided	research
University of Washington Center for Mendelian Genomics, University of Washington	RCV001258011	SCV001434825	likely pathogenic	Congenital cerebellar hypoplasia		no assertion criteria provided	research