ClinVar Miner

Submissions for variant NM_001165963.4(SCN1A):c.4555C>A (p.Pro1519Thr) (rs796053021)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000188963 SCV000242594 uncertain significance not provided 2017-09-19 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the SCN1A gene. The P1519T variant has previously reported in an individual with Dravet syndrome, however parental testing was not reported (Moehring et al., 2013). The P1519T variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The P1519T 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 conserved position predicted to be within the cytoplasmic loop between third and fourth homologous domains. In silico analysis predicts this variant is probably damaging to the protein structure/function. Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000818881 SCV000959518 uncertain significance Early infantile epileptic encephalopathy 2018-11-08 criteria provided, single submitter clinical testing This sequence change replaces proline with threonine at codon 1519 of the SCN1A protein (p.Pro1519Thr). The proline residue is highly conserved and there is a small physicochemical difference between proline and threonine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with Dravet syndrome (PMID: 23398550). ClinVar contains an entry for this variant (Variation ID: 206838). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Epilepsy and Neurogenetic Laboratory,Kaohsiung Chang Gung Memorial Hospital RCV001254862 SCV001190015 likely pathogenic Generalized epilepsy with febrile seizures plus, type 2 2020-02-28 criteria provided, single submitter research The missense variant is identified in a proband presented with Genetic Epilepsy with Febrile Seizure Plus without developmental delay. The variant is inherited from the affected father who also have FS. There are other members in the paternal side known to have FS. According to ACMG guidelines, this variant is classified as likely pathogenic due to PM1: Located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation; PM2: Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium; PP1: Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease; PP3: Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).

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