ClinVar Miner

Submissions for variant NM_001040142.2(SCN2A):c.2558G>A (p.Arg853Gln) (rs794727152)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000174944 SCV000226350 pathogenic not provided 2015-03-18 criteria provided, single submitter clinical testing
GeneDx RCV000174944 SCV000242746 pathogenic not provided 2017-03-23 criteria provided, single submitter clinical testing The R853Q variant in the SCN2A gene has been reported as a confirmed or assumed de novo substitution in multiple unrelated patients with West syndrome or Lennox-Gastaut syndrome who also exhibited hypotonia, developmental delay, and/or movement disorders (Allen et al., 2013; Nakamura et al., 2013; Kobayashi et al., 2016). This variant was not observed in approximately 6500 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 R853Q subsitution is a non-conservative amino acid substitution that occurs at a conserved position in the voltage-sensing S4 transmembrane segment of the second homologous domain. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret R853Q as a pathogenic variant.
UCLA Clinical Genomics Center, UCLA RCV000197677 SCV000255457 likely pathogenic Early infantile epileptic encephalopathy 11 2013-06-18 criteria provided, single submitter clinical testing
Groupe Hospitalier Pitie Salpetriere, UF Genomique du Developpement,Assistance Publique Hopitaux de Paris RCV000197677 SCV000586759 pathogenic Early infantile epileptic encephalopathy 11 2017-01-06 criteria provided, single submitter clinical testing Intellectual disability.severe; epilepsy (spasms); dysmorphism
Fulgent Genetics,Fulgent Genetics RCV000515237 SCV000611316 pathogenic Benign familial neonatal-infantile seizures; Early infantile epileptic encephalopathy 11 2017-05-18 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000174944 SCV000843638 pathogenic not provided 2017-10-31 criteria provided, single submitter clinical testing
Invitae RCV000515237 SCV000950141 pathogenic Benign familial neonatal-infantile seizures; Early infantile epileptic encephalopathy 11 2019-11-14 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 853 of the SCN2A protein (p.Arg853Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with West syndrome, including at least three individuals where the variant was reported de novo (PMID: 25772804, 28379373, 23935176, 29186148). ClinVar contains an entry for this variant (Variation ID: 194555). 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: "Possibly Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic.
Centogene AG - the Rare Disease Company RCV000197677 SCV001426566 pathogenic Early infantile epileptic encephalopathy 11 criteria provided, single submitter clinical testing

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