ClinVar Miner

Submissions for variant NM_001330260.2(SCN8A):c.3103G>A (p.Asp1035Asn)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Neuberg Centre For Genomic Medicine, NCGM RCV002510751 SCV002820311 uncertain significance Developmental and epileptic encephalopathy, 13 criteria provided, single submitter clinical testing The missense variant p.D1035N in SCN8A (NM_014191.3) has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The missense variant c.3103G>A (p.D1035N) in SCN8A (NM_014191.4) is observed in 8/30574 (0.0262%) alleles from individuals of South Asian background in the gnomAD dataset (Exome Aggregation Consortium et al., 2016), but was not seen in the homozygous state. The p.D1035N missense variant is predicted to be damaging by both SIFT and PolyPhen2. The nucleotide c.3103 in SCN8A is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance.
Labcorp Genetics (formerly Invitae), Labcorp RCV003776050 SCV004672022 uncertain significance Early infantile epileptic encephalopathy with suppression bursts 2023-08-30 criteria provided, single submitter clinical testing This variant is present in population databases (rs571608674, gnomAD 0.03%). This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 1035 of the SCN8A protein (p.Asp1035Asn). This variant has not been reported in the literature in individuals affected with SCN8A-related conditions. 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. 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 SCN8A protein function. ClinVar contains an entry for this variant (Variation ID: 1878660).

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