ClinVar Miner

Submissions for variant NM_001040142.2(SCN2A):c.1399G>A (p.Ala467Thr)

gnomAD frequency: 0.00004  dbSNP: rs745774658
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000522032 SCV000621281 likely benign not provided 2019-03-26 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 29635106)
CeGaT Center for Human Genetics Tuebingen RCV000522032 SCV001152478 uncertain significance not provided 2016-08-01 criteria provided, single submitter clinical testing
Invitae RCV001214677 SCV001386371 uncertain significance Seizures, benign familial infantile, 3; Developmental and epileptic encephalopathy, 11 2023-12-18 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 467 of the SCN2A protein (p.Ala467Thr). This variant is present in population databases (rs745774658, gnomAD 0.02%). This missense change has been observed in individuals with clinical features of SCN2A-related conditions (PMID: 29635106; Invitae). In some individuals, the variant was inherited from an unaffected parent. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 452471). 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 SCN2A 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 RCV001542304 SCV001760989 uncertain significance Developmental and epileptic encephalopathy, 11 2020-07-10 criteria provided, single submitter clinical testing The inherited c.1399G>A (p.Ala467Thr) variant identified in the SCN2A gene substitutes a moderately conserved Alanine for Threonine at amino acid 467/2006 (exon 11/27). Threonine is present at this position in several smaller vertebrates including some species of bird and bat. This variant is found with low frequency in gnomAD(v3.0) (5 heterozygotes, 0 homozygotes; allele frequency: 3.49e-5) suggesting it is not a common benign variant in the populations represented in that database. In silico algorithms predict this variant to be Deleterious (Provean; score:-0.42) and Damaging (SIFT; score:0.363) to the function of the canonical transcript. The c.1399G>A (p.Ala467Thr) variant is reported in ClinVar as a Variant of Uncertain Significance (VarID:452471), and has been reported in one family with SCN2A-associated seizure disorder [PMID:29635106]. The p.Ala467 residue is not within a mapped domain of SCN2A (UniProtKB:Q99250). Given the lack of compelling evidence for its pathogenicity, the inherited c.1399G>A (p.Ala467Thr) variant identified in the SCN2A gene is reported as a Variant of Uncertain Significance.
Revvity Omics, Revvity RCV000522032 SCV003820757 uncertain significance not provided 2019-12-09 criteria provided, single submitter clinical testing

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