ClinVar Miner

Submissions for variant NM_006920.6(SCN1A):c.4096A>G (p.Ile1366Val) (rs762317674)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 4
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000718675 SCV000849539 likely benign History of neurodevelopmental disorder 2017-05-09 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Other data supporting benign classification,In silico models in agreement (benign)
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000725944 SCV000340713 uncertain significance not provided 2016-04-19 criteria provided, single submitter clinical testing
GeneDx RCV000725944 SCV000589462 uncertain significance not provided 2019-01-14 criteria provided, single submitter clinical testing The I1377V variant has not been published as a pathogenic variant, nor has it been reported as a benign polymorphism to our knowledge. It 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. This substitution alters a position where amino acids with similar properties to Isoleucine are tolerated across species, and is predicted to be in the transmembrane segment S5 in the third homologous domain. Missense variants in nearby residues (G1371V, K1372E, C1376R) have been reported in the Human Gene Mutation Database in association with SCN1A-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. However, the I1377V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties, and in silico analysis predicts this variant likely does not alter the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000794768 SCV000934196 uncertain significance Early infantile epileptic encephalopathy 2018-11-27 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 1377 of the SCN1A protein (p.Ile1377Val). The isoleucine residue is moderately conserved and there is a small physicochemical difference between isoleucine and valine. This variant is present in population databases (rs762317674, ExAC 0.02%). This variant has not been reported in the literature in individuals with SCN1A-related conditions. ClinVar contains an entry for this variant (Variation ID: 287064). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The valine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.