ClinVar Miner

Submissions for variant NM_001365536.1(SCN9A):c.2576T>C (p.Ile859Thr) (rs80356474)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001067998 SCV001233085 pathogenic Hereditary sensory and autonomic neuropathy type IIA; Generalized epilepsy with febrile seizures plus, type 7 2019-12-11 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 848 of the SCN9A protein (p.Ile848Thr). The isoleucine residue is highly conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with autosomal dominant primary erythromelalgia (PMID: 14985375, 29911575). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 6350). This variant has been reported to affect SCN9A protein function (PMID: 15385606). For these reasons, this variant has been classified as Pathogenic.
Illumina Clinical Services Laboratory,Illumina RCV001270748 SCV001451497 pathogenic SCN9A-related peripheral neuropathies associated with increased pain 2019-03-12 criteria provided, single submitter clinical testing The SCN9A c.2543T>C (p.Ile848Thr) variant is a missense variant and has been reported in at least seven studies, in which it is found in a heterozygous state in a total of 10 individuals with inherited erythromelalgia (Yang et al. 2004; Drenth et al. 2005; Drenth et al. 2008; Natkunarajah et al. 2009; Zhang et al. 2014; Namer et al. 2015; McDonnell et al. 2016). The age of onset was reported at three to five years in individuals carrying the p.Ile848Thr variant. In two families, the variant was shown to segregate with disease. The p.Ile848Thr variant was absent from 350 control subjects and is not found in the Genome Aggregation Database, in a region of good sequence coverage, so the variant is presumed to be rare. Functional studies in C-fibers from a patient carrying the p.Ile848Thr variant demonstrated an enhanced early subnormal conduction in the velocity recovery cycles (Namer et al. 2015). In addition, HEK293 cells expressing this variant exhibited altered sodium channel function compared to wild type (Cummins et al. 2004). Based on the collective evidence and application of the ACMG criteria, the p.Ile848Thr variant is classified as pathogenic for SCN9A-related peripheral neuropathies associated with increased pain.
OMIM RCV000006722 SCV000026913 pathogenic Primary erythromelalgia 2004-09-22 no assertion criteria provided literature only
GeneReviews RCV000006722 SCV000040964 pathogenic Primary erythromelalgia 2020-01-14 no assertion criteria provided literature only
NIHR Bioresource Rare Diseases, University of Cambridge RCV001004018 SCV001162079 likely pathogenic Acute episodes of neuropathic symptoms; Abnormality of pain sensation no assertion criteria provided research

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