ClinVar Miner

Submissions for variant NM_001040142.2(SCN2A):c.3780G>T (p.Lys1260Asn)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV003810098 SCV004607958 uncertain significance Seizures, benign familial infantile, 3; Developmental and epileptic encephalopathy, 11 2023-08-07 criteria provided, single submitter clinical testing 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 expected to disrupt SCN2A protein function. This variant has not been reported in the literature in individuals affected with SCN2A-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 1260 of the SCN2A protein (p.Lys1260Asn).
Ambry Genetics RCV004366669 SCV004944216 uncertain significance Inborn genetic diseases 2023-10-24 criteria provided, single submitter clinical testing The c.3780G>T (p.K1260N) alteration is located in exon 20 (coding exon 19) of the SCN2A gene. This alteration results from a G to T substitution at nucleotide position 3780, causing the lysine (K) at amino acid position 1260 to be replaced by an asparagine (N). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). Two other alterations at the same codon, c.3778A>C (p.K1260Q) and c.3778A>G (p.K1260E), have been detected in a mosaic state in one individual with early infantile epileptic encephalopathy (Trump, 2016). This amino acid position is highly conserved in available vertebrate species. The in silico prediction for this alteration is inconclusive. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

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