ClinVar Miner

Submissions for variant NM_002977.3(SCN9A):c.2686C>T (p.Arg896Trp) (rs202152511)

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Total submissions: 2
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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 2018-09-12 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 not been reported in the literature in individuals with SCN9A-related disease. ClinVar contains an entry for this variant (Variation ID: 421969). 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 disruptive, 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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