ClinVar Miner

Submissions for variant NM_002977.3(SCN9A):c.1555G>A (p.Glu519Lys) (rs187453572)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital RCV000781948 SCV000920392 uncertain significance Seizures 2017-08-25 no assertion criteria provided clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000723961 SCV000225304 uncertain significance not provided 2015-09-09 criteria provided, single submitter clinical testing
GeneDx RCV000723961 SCV000617190 uncertain significance not provided 2018-07-27 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the SCN9A gene. The E519K variant has been previously reported as a maternally inherited variant in a patient with Dravet syndrome; the clinical significance is uncertain (Singh et al., 2009). To our knowledge, this variant has not been previously reported in association with small fiber neuropathy or congenital indifference to pain. The E519K variant is not observed 48/66670 (0.07%) alleles from individuals of European background in large population cohorts (Lek et al., 2016). The E519K 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. However, this substitution occurs at a position that is not conserved. In silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Illumina Clinical Services Laboratory,Illumina RCV000317826 SCV000418693 likely benign Generalized epilepsy with febrile seizures plus 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000388718 SCV000418694 likely benign Paroxysmal extreme pain disorder 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000277449 SCV000418695 likely benign Small fiber neuropathy 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000330745 SCV000418696 likely benign Severe myoclonic epilepsy in infancy 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000387570 SCV000418697 likely benign Familial Febrile Seizures 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000290806 SCV000418698 likely benign Congenital Indifference to Pain 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000348148 SCV000418699 likely benign Inherited Erythromelalgia 2016-06-14 criteria provided, single submitter clinical testing
Invitae RCV000468717 SCV000548352 uncertain significance Hereditary sensory and autonomic neuropathy type IIA; Generalized epilepsy with febrile seizures plus, type 7 2018-12-19 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 519 of the SCN9A protein (p.Glu519Lys). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs187453572, ExAC 0.07%). This variant has been reported in an individual affected with Dravet syndrome who did not have an SCN1A variant (PMID: 19763161). ClinVar contains an entry for this variant (Variation ID: 193859). 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 tolerated, 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.

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