ClinVar Miner

Submissions for variant NM_001165963.4(SCN1A):c.5978T>C (p.Ile1993Thr)

gnomAD frequency: 0.00002  dbSNP: rs766656231
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000818688 SCV000959314 uncertain significance Early infantile epileptic encephalopathy with suppression bursts 2023-11-18 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 1993 of the SCN1A protein (p.Ile1993Thr). This variant is present in population databases (rs766656231, gnomAD 0.008%). This variant has not been reported in the literature in individuals affected with SCN1A-related conditions. ClinVar contains an entry for this variant (Variation ID: 661300). 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) performed at Invitae indicates that this missense variant is not expected to disrupt SCN1A protein function with a negative predictive value of 95%. 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.
New York Genome Center RCV001281561 SCV001468871 uncertain significance Seizure; Intellectual disability 2019-07-25 criteria provided, single submitter clinical testing The p.Ile1993Thr variant identified in the SCN1A gene has not been reported in affected individuals in the literature. The variant has 0.0000071 allele frequency in the gnomAD database (2 out of 282,146 heterozygous alleles) indicatingit is an extremely rare allele in the populations represented in that database. The variant affects residue number 1993 located in the C-terminal region of 2009-amino-acid polypeptide and is predicted “tolerated” by SIFT and PolyPhen2. Based on the current evidence, the p.Ile1993Thr variant in the SCN1A gene is assessed as a variant of uncertain significance.

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