ClinVar Miner

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

dbSNP: rs398123695
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Total submissions: 5
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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

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