ClinVar Miner

Submissions for variant NM_001365536.1(SCN9A):c.1604C>T (p.Ser535Leu) (rs201354321)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000647800 SCV000769603 uncertain significance Hereditary sensory and autonomic neuropathy type IIA; Generalized epilepsy with febrile seizures plus, type 7 2020-09-24 criteria provided, single submitter clinical testing This sequence change replaces serine with leucine at codon 535 of the SCN9A protein (p.Ser535Leu). The serine residue is highly conserved and there is a large physicochemical difference between serine and leucine. This variant is present in population databases (rs201354321, ExAC 0.002%). This variant has not been reported in the literature in individuals with SCN9A-related disease. 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.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000757742 SCV000886081 uncertain significance not provided 2017-09-26 criteria provided, single submitter clinical testing The p.Ser535Leu variant (rs201354321) has not been reported in the medical literature, gene specific variation databases, nor has it been previously identified by our laboratory. This variant is listed in the Genome Aggregation Database (gnomAD) with an overall population frequency of 0.002 percent (identified on 4 out of 260,912 chromosomes). The serine at position 535 is highly conserved considering 12 species (Alamut v2.9.0) and computational analyses of the effects of the p.Ser535Leu variant on protein structure and function indicate a deleterious effect (SIFT: damaging, MutationTaster: disease causing, PolyPhen-2: probably damaging). Altogether, there is not enough evidence to classify the p.Ser535Leu variant with certainty.
Fulgent Genetics,Fulgent Genetics RCV000765527 SCV000896841 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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