ClinVar Miner

Submissions for variant NM_006920.6(SCN1A):c.3935C>A (p.Pro1312His) (rs1057521746)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000720045 SCV000850921 likely pathogenic History of neurodevelopmental disorder 2017-04-28 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Rarity in general population databases (dbsnp, esp, 1000 genomes),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Structural Evidence
GeneDx RCV000430833 SCV000524399 likely pathogenic not provided 2016-02-25 criteria provided, single submitter clinical testing A published P1323H variant that is likely pathogenic has been identified in the SCN1A gene. TheP1323H variant has been reported previously as a de novo variant in an individual with Dravetsyndrome (Specchio et al., 2014). It was not observed in approximately 6,500 individuals of Europeanand African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not acommon benign variant in these populations. The P1323H variant is a non-conservative amino acidsubstitution, which is likely to impact secondary protein structure as these residues differ in polarity,charge, size and/or other properties. This substitution occurs at a conserved position predicted to bewithin the voltage-sensor transmembrane segment S4 of the third homologous domain of the SCN1Aprotein. Different missense variants at the same position (P1323R, P1323S) as well as multiplemissense variants in nearby residues have been reported in association with SCN1A-related disorders(Stenson et al., 2014; SCN1A Variant Database), supporting the functional importance of this regionof the protein. In silico analysis predicts this variant is probably damaging to the proteinstructure/function. Therefore, this variant is likely pathogenic; however, the possibility that it isbenign cannot be excluded.

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