ClinVar Miner

Submissions for variant NM_001365536.1(SCN9A):c.5858C>T (p.Thr1953Ile)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001174605 SCV001337799 uncertain significance not specified 2020-12-07 criteria provided, single submitter clinical testing Variant summary: SCN9A c.5825C>T (p.Thr1942Ile) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 248302 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.5825C>T has been reported in the literature in one family affected with Paroxysmal Extreme Pain Disorder (Jerez_2019). Specifically, the variant was detected in two affected family members (proband and father) but also, in an unaffected family member (older brother of the proband). This report does not provide unequivocal conclusions about association of the variant with Primary erythromelalgia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae RCV001300847 SCV001489997 uncertain significance Hereditary sensory and autonomic neuropathy type IIA; Generalized epilepsy with febrile seizures plus, type 7 2020-03-17 criteria provided, single submitter clinical testing This sequence change replaces threonine with isoleucine at codon 1942 of the SCN9A protein (p.Thr1942Ile). The threonine residue is moderately conserved and there is a moderate physicochemical difference between threonine and isoleucine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with SCN9A-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: Tolerated; PolyPhen-2: Benign; Align-GVGD: Class C0. The isoleucine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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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