ClinVar Miner

Submissions for variant NM_001365536.1(SCN9A):c.2719C>T (p.Arg907Trp) (rs202152511)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 3
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000479461 SCV000571318 likely pathogenic not provided 2016-08-12 criteria provided, single submitter clinical testing A novel R896W variant that is likely pathogenic has been identified in the SCN9A gene. The R896W variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge, but a different missense variant at the same position (R896Q) has been reported previously in association with congenital indifference to pain (Cox et al., 2010). The R896W variant was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. The R896W 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 conserved position predicted to be within in the extracellular loop between the S5 and S6 transmembrane segments of the second homologous domain. In silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Invitae RCV000700015 SCV000828750 uncertain significance Hereditary sensory and autonomic neuropathy type IIA; Generalized epilepsy with febrile seizures plus, type 7 2020-03-06 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 896 of the SCN9A protein (p.Arg896Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been observed in individual(s) with autosomal recessive congenital insensitivity to pain (PMID: 30795902). ClinVar contains an entry for this variant (Variation ID: 421969). This variant has been reported to affect SCN9A protein function (PMID: 30795902). This variant disrupts the p.Arg896 amino acid residue in SCN9A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20635406, 29978519). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.
GenomeConnect - Invitae Patient Insights Network RCV001535622 SCV001749648 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 05-11-2018 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.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.