ClinVar Miner

Submissions for variant NM_001365536.1(SCN9A):c.1846G>A (p.Gly616Arg) (rs201338643)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000544928 SCV000649283 uncertain significance Hereditary sensory and autonomic neuropathy type IIA; Generalized epilepsy with febrile seizures plus, type 7 2019-11-19 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 616 of the SCN9A protein (p.Gly616Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is present in population databases (rs201338643, ExAC 0.01%). This variant has been reported in 3 affected and 1 unaffected individuals in a family affected with inherited erythromelalgia (PMID: 20478850). ClinVar contains an entry for this variant (Variation ID: 433099). Experimental studies in vitro in transfected dorsal root ganglion neurons have shown that this missense change impacts the channel function of the adult-long splicing isoform of SCN9A (PMID: 20478850). 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. 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.
GeneDx RCV001557778 SCV001779605 uncertain significance not provided 2019-08-05 criteria provided, single submitter clinical testing Reported previously in the heterozygous state in three related individuals with erythromelagia (Choi et al., 2010); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 26220970, 30416015, 20478850, 28150151)
Bioinformatics Core,Luxembourg Center for Systems Biomedicine RCV000655988 SCV000588264 pathogenic Rolandic epilepsy 2017-01-01 no assertion criteria provided case-control CAADphred>15
GenomeConnect - Invitae Patient Insights Network RCV001535614 SCV001749635 not provided Primary erythromelalgia; Hereditary sensory and autonomic neuropathy type IIA; Paroxysmal extreme pain disorder; Indifference to pain, congenital, autosomal recessive; Generalized epilepsy with febrile seizures plus no assertion provided phenotyping only Variant interpreted as Uncertain significance and reported on 04-05-2018 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.

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