ClinVar Miner

Submissions for variant NM_002977.3(SCN9A):c.3911T>C (p.Ile1304Thr) (rs202235611)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000389225 SCV000418382 uncertain significance Severe myoclonic epilepsy in infancy 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000276112 SCV000418383 uncertain significance Paroxysmal extreme pain disorder 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000316360 SCV000418384 uncertain significance Familial febrile seizures 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000375646 SCV000418385 uncertain significance Congenital Indifference to Pain 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000281022 SCV000418386 uncertain significance Generalized epilepsy with febrile seizures plus 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000340680 SCV000418387 uncertain significance Inherited Erythromelalgia 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000376885 SCV000418388 uncertain significance Small fiber neuropathy 2016-06-14 criteria provided, single submitter clinical testing
GeneDx RCV000412791 SCV000492430 uncertain significance not provided 2016-12-09 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the SCN9A gene. The I1304T variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The I1304T variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The I1304T 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 occurs at a position in transmembrane segment S4 in the 3rd homologous domain at a position that is not conserved across species. 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 RCV000647772 SCV000769575 uncertain significance Hereditary sensory and autonomic neuropathy type IIA; Generalized epilepsy with febrile seizures plus, type 7 2018-08-22 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 1304 of the SCN9A protein (p.Ile1304Thr). The isoleucine residue is moderately conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is present in population databases (rs202235611, ExAC 0.02%). This variant has not been reported in the literature in individuals with SCN9A-related disease. ClinVar contains an entry for this variant (Variation ID: 331965). 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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