ClinVar Miner

Submissions for variant NM_001365536.1(SCN9A):c.4043A>G (p.Tyr1348Cys)

gnomAD frequency: 0.00001  dbSNP: rs587780456
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory, University of Chicago RCV000118306 SCV000152680 uncertain significance not provided 2013-08-27 criteria provided, single submitter clinical testing
Invitae RCV001053070 SCV001217312 uncertain significance Neuropathy, hereditary sensory and autonomic, type 2A; Generalized epilepsy with febrile seizures plus, type 7 2023-12-21 criteria provided, single submitter clinical testing This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 1337 of the SCN9A protein (p.Tyr1337Cys). This variant is present in population databases (rs587780456, gnomAD 0.009%). This variant has not been reported in the literature in individuals affected with SCN9A-related conditions. ClinVar contains an entry for this variant (Variation ID: 130268). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SCN9A protein function with a negative predictive value of 80%. 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.
Ambry Genetics RCV002354302 SCV002622146 uncertain significance Inborn genetic diseases 2020-02-21 criteria provided, single submitter clinical testing The p.Y1337C variant (also known as c.4010A>G), located in coding exon 21 of the SCN9A gene, results from an A to G substitution at nucleotide position 4010. The tyrosine at codon 1337 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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