ClinVar Miner

Submissions for variant NM_001165963.4(SCN1A):c.5218G>A (p.Asp1740Asn) (rs796053035)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000188995 SCV000242626 likely pathogenic not provided 2018-08-28 criteria provided, single submitter clinical testing p.Asp1740Asn (GAC>AAC): c.5218 G>A in exon 26 of the SCN1A gene (NM_001165963.1) The D1740N variant 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 D1740N variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution alters a highly conserved position in the extracellular loop between the S5 and S6 transmembrane segments of the fourth homologous domain of the SCN1A protein (Escayg et al., 2010), and multiple missense mutations have been reported in this region of the protein in association with epilepsy in an external mutation database, supporting the functional importance of this region of the protein. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, this variant is a strong candidate for a pathogenic mutation, however the possibility that it is a benign variant cannot be excluded. The variant is found in EPILEPSY panel(s).
Integrated Genetics/Laboratory Corporation of America RCV000781836 SCV000920185 likely pathogenic Autosomal dominant epilepsy 2018-05-30 criteria provided, single submitter clinical testing Variant summary: SCN1A c.5218G>A (p.Asp1740Asn) results in a conservative amino acid change located in the Ion transport domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 246008 control chromosomes (gnomAD). The variant, c.5218G>A, was found to segregate within a SCN1A-Related Seizure Disorder family (Zhang_2017). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Invitae RCV001210054 SCV001381518 pathogenic Early infantile epileptic encephalopathy 2019-11-14 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with asparagine at codon 1740 of the SCN1A protein (p.Asp1740Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with clinical features of clinical features of genetic epilepsy with febrile seizures plus and/or neurodevelopmental disorders (PMID: 28842445, 29655203, Invitae). This variant has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 206861). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). For these reasons, this variant has been classified as Pathogenic.

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