ClinVar Miner

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

gnomAD frequency: 0.00006  dbSNP: rs192406412
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000221632 SCV000279637 uncertain significance not provided 2023-06-22 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Invitae RCV000692363 SCV000820181 uncertain significance Neuropathy, hereditary sensory and autonomic, type 2A; Generalized epilepsy with febrile seizures plus, type 7 2024-01-27 criteria provided, single submitter clinical testing This sequence change replaces leucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 427 of the SCN9A protein (p.Leu427Ser). This variant is present in population databases (rs192406412, gnomAD 0.01%). 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: 234638). 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 95%. 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; Neuropathy, hereditary sensory and autonomic, type 2A; Paroxysmal extreme pain disorder; Severe myoclonic epilepsy in infancy; Channelopathy-associated congenital insensitivity to pain, autosomal recessive; Generalized epilepsy with febrile seizures plus, type 7 2018-10-31 criteria provided, single submitter clinical testing
Baylor Genetics RCV001336519 SCV001529921 uncertain significance Generalized epilepsy with febrile seizures plus, type 7 2018-07-16 criteria provided, single submitter clinical testing This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Ambry Genetics RCV002381753 SCV002695199 uncertain significance Inborn genetic diseases 2021-11-18 criteria provided, single submitter clinical testing The p.L427S variant (also known as c.1280T>C), located in coding exon 9 of the SCN9A gene, results from a T to C substitution at nucleotide position 1280. The leucine at codon 427 is replaced by serine, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this variant is unlikely to be causative of autosomal dominant SCN9A-related neuropathic pain syndromes; however, its contribution to the development of autosomal recessive congenital insensitivity to pain is uncertain.

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