Submissions for variant NM_001040142.2(SCN2A):c.5732T>C (p.Ile1911Thr)

dbSNP: rs2105403778

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001766050	SCV002007834	uncertain significance	not provided	2019-07-25	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek et al., 2016); The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge; This substitution is predicted to be within the C-terminal cytoplasmic domain.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003772071	SCV004591888	uncertain significance	Seizures, benign familial infantile, 3; Developmental and epileptic encephalopathy, 11	2023-11-22	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1911 of the SCN2A protein (p.Ile1911Thr). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SCN2A-related conditions. ClinVar contains an entry for this variant (Variation ID: 1316144). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SCN2A protein function. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004690130	SCV005184657	uncertain significance	not specified	2024-05-24	criteria provided, single submitter	clinical testing	Variant summary: SCN2A c.5732T>C (p.Ile1911Thr) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250658 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.5732T>C in individuals affected with Early Infantile Epileptic Encephalopathy 11 and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 1316144). Based on the evidence outlined above, the variant was classified as uncertain significance.