Submissions for variant NM_005639.3(SYT1):c.1103T>C (p.Ile368Thr)

dbSNP: rs1135402761

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV000497062	SCV000588405	likely pathogenic	not provided	2017-07-13	criteria provided, single submitter	research
Raymond Lab, University of Cambridge	RCV000721124	SCV000852012	pathogenic	SYT1-associated neurodevelopmental disorder	2018-07-01	criteria provided, single submitter	research
SIB Swiss Institute of Bioinformatics	RCV000735268	SCV000994935	likely pathogenic	Infantile hypotonia-oculomotor anomalies-hyperkinetic movements-developmental delay syndrome	2019-02-18	criteria provided, single submitter	curation	This variant is interpreted as a Likely pathogenic for Baker-Gordon syndrome, autosomal dominant. The following ACMG Tag(s) were applied: PM2: Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PM6: Assumed de novo, but without confirmation of paternity and maternity. PS3-Moderate: Well-established functional studies show a deleterious effect (downgraded to Moderate). PM1: Located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation. PS4-Supporting: Prevalence in affecteds statistically increased over controls (downgraded to Supporting).
CeGaT Center for Human Genetics Tuebingen	RCV000497062	SCV001246557	pathogenic	not provided	2021-06-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002527129	SCV003620268	pathogenic	Inborn genetic diseases	2022-06-13	criteria provided, single submitter	clinical testing	The c.1103T>C (p.I368T) alteration is located in exon 12 (coding exon 8) of the SYT1 gene. This alteration results from a T to C substitution at nucleotide position 1103, causing the isoleucine (I) at amino acid position 368 to be replaced by a threonine (T). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration has been reported de novo in multiple patients with neurodevelopmental disorders that included global developmental delay, intellectual disability, hypotonia, dyskinetic movements, and behavior disorder. Additional features included talipes and nystagmus or esotropia (Baker, 2015; Baker, 2018; Melland, 2022). This amino acid position is highly conserved in available vertebrate species. In vivo assessment of a child with a heterozygous I368T SYT1 mutation and in vitro investigation of the mutation in isolated mouse neurons showed abnormal kinetics of neurophysiological function (Baker, 2015). Using immunocytochemistry and electrophysiological recordings of synaptic currents in cultured mouse hippocampal and cortical neurons, Bradberry et. al. (2020) showed synaptic transmission was impaired in neurons expressing this mutant variant, demonstrating potent, graded dominant-negative effects. The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic.
OMIM	RCV000735268	SCV000863516	pathogenic	Infantile hypotonia-oculomotor anomalies-hyperkinetic movements-developmental delay syndrome	2018-12-12	no assertion criteria provided	literature only