ClinVar Miner

Submissions for variant NM_001165963.4(SCN1A):c.2552A>G (p.Asn851Ser) (rs561912072)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000188891 SCV000242521 uncertain significance not provided 2013-06-11 criteria provided, single submitter clinical testing p.Asn851Ser (AAT>AGT): c.2552 A>G in exon 14 of the SCN1A gene (NM_001165963.1) The Asn851Ser missense change has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The amino acid substitution is conservative as both Asparagine and Serine are uncharged, polar amino acid residues. Asn851Ser alters a poorly conserved position between the third and fourth segments of the second transmembrane domain in the protein. However, another missense variant in this region of the protein (Glu853Lys) has been published as a de novo mutation in an individual with myoclonic epilepsy in infancy (Mancardi et al., 2006). In addition, while two in-silico algorithms predict Asn851Ser is non-pathogenic, another model predicts it may be damaging to the structure/function of the protein. Therefore, based on the currently available information, it is unclear whether Asn851Ser is a disease-causing mutation or a rare benign variant. The variant is found in EPILEPSY panel(s).
LifeCell International Pvt. Ltd RCV001527713 SCV001738768 uncertain significance Severe myoclonic epilepsy in infancy criteria provided, single submitter clinical testing A heterozygous missense variant (c.2552A>G) in exon 17 of the SCN1A gene that results in the amino acid substitution from Asparagine to Serine at codon 851 (p.Asn851Ser) was identified. The observed variant is reported in both the 1000 Genomes and gnomAD databases with minor allele frequency of 0.0200% and 0.0016% respectively. The reference base is conserved in mammals and in-silico predictions by SIFT is damaging. The Missense Variants Z-Score for this variant is 5.61. Missense Variants Z-Score is produced by the Exome Aggregation Consortium (60,706 adult humans) by computing a signed Z score for the deviation of observed counts from the expected number. Positive Z scores indicate increased constraint (intolerance to variation) and therefore that the gene had fewer missense variants than expected. (DOI: 10.1038/nature19057). Based on the above evidence this variant has been classified as variant of uncertain significance according to the ACMG guidelines.

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