Submissions for variant NM_006950.3(SYN1):c.1372C>G (p.Gln458Glu)

gnomAD frequency: 0.00011  dbSNP: rs372445055

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000189656	SCV000243302	uncertain significance	not provided	2017-11-01	criteria provided, single submitter	clinical testing	p.Gln458Glu (CAG>GAG): c.1372 C>G in the SYN1 gene. The Gln458Glu missense change has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The amino acid substitution is non-conservative, as an uncharged Glutamine residue is replaced by a negatively charged Glutamic acid residue. It alters a highly conserved position in the protein, although other missense mutations have not been reported in this region of the protein. Several in silico algorithms predict Gln458Glu may be benign, while another model suggests it may be damaging to protein structure/function. Therefore, based on the currently available information, it is unclear whether Gln458Glu is a disease-causing mutation or a rare benign variant. The variant is found in EPILEPSY, INFANT-EPI panel(s).
Labcorp Genetics (formerly Invitae), Labcorp	RCV001323946	SCV001514881	uncertain significance	Epilepsy, X-linked 1, with variable learning disabilities and behavior disorders	2025-01-08	criteria provided, single submitter	clinical testing	This sequence change replaces glutamine, which is neutral and polar, with glutamic acid, which is acidic and polar, at codon 458 of the SYN1 protein (p.Gln458Glu). This variant is present in population databases (rs372445055, gnomAD 0.01%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with SYN1-related conditions. ClinVar contains an entry for this variant (Variation ID: 207472). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV002381643	SCV002697654	likely benign	Inborn genetic diseases	2022-10-25	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Fulgent Genetics, Fulgent Genetics	RCV002478663	SCV002781834	uncertain significance	Epilepsy, X-linked 1, with variable learning disabilities and behavior disorders; Intellectual disability, X-linked 50	2022-01-25	criteria provided, single submitter	clinical testing
GenomeConnect - Brain Gene Registry	RCV002225495	SCV002505373	not provided	X-linked complex neurodevelopmental disorder		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 09-22-2021 by Lab or GTR ID 505538. Variant identified in multiple related participants. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator John Constantino MD PhD from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/.