ClinVar Miner

Submissions for variant NM_001365536.1(SCN9A):c.1280T>C (p.Leu427Ser) (rs192406412)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000221632 SCV000279637 uncertain significance not provided 2016-07-07 criteria provided, single submitter clinical testing The L427S variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The L427S variant was not observed with any significant frequency in approximately 5,900 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project or in the 1000 Genomes Project. The L427S 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 alters a conserved position predicted to be in the loop between the first and second homologous domains of the SCN9A protein. In silico analysis predicts this variant is probably damaging to the protein structure/function. However, missense variants in nearby residues have not been reported in the Human Gene Mutation Database in association with SCN9A-related disorders (Stenson et al., 2014). Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benignvariant.
Invitae RCV000692363 SCV000820181 uncertain significance Hereditary sensory and autonomic neuropathy type IIA; Generalized epilepsy with febrile seizures plus, type 7 2019-11-25 criteria provided, single submitter clinical testing This sequence change replaces leucine with serine at codon 427 of the SCN9A protein (p.Leu427Ser). The leucine residue is highly conserved and there is a large physicochemical difference between leucine and serine. This variant is present in population databases (rs192406412, ExAC 0.003%). This variant has not been reported in the literature in individuals with SCN9A-related disease. ClinVar contains an entry for this variant (Variation ID: 234638). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.
Fulgent Genetics,Fulgent Genetics RCV000765528 SCV000896842 uncertain significance Primary erythromelalgia; Hereditary sensory and autonomic neuropathy type IIA; Paroxysmal extreme pain disorder; Severe myoclonic epilepsy in infancy; Indifference to pain, congenital, autosomal recessive; Generalized epilepsy with febrile seizures plus, type 7 2018-10-31 criteria provided, single submitter clinical testing

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