ClinVar Miner

Submissions for variant NM_001365536.1(SCN9A):c.1675G>A (p.Gly559Ser) (rs201569378)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000492905 SCV000582907 uncertain significance not provided 2017-05-19 criteria provided, single submitter clinical testing The G559S variant in the SCN9A gene has been reported previously in a patient with epilepsy; however, the patient also harbored a de novo variant in a gene known to cause epilepsy (Mulley et al., 2013). In addition, the G559S variant is observed in 10/66,118 alleles (0.015%) from individuals of non-Finnish European background in the ExAC dataset, with no homozygous control individuals reported (Lek et al., 2016). However, the G559S 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 also occurs at a position that is conserved across mammalian species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, we interpret G559S as a variant of uncertain significance.
Invitae RCV000647785 SCV000769588 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 glycine with serine at codon 559 of the SCN9A protein (p.Gly559Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. This variant is present in population databases (rs201569378, ExAC 0.02%). This variant has been observed in an individual with Dravet syndrome (PMID: 23895530). However, in that individual a de novo variant was also identified in SCN1A, which suggests that this c.1675G>A variant was not the primary cause for epilepsy, and the involvement of the SCN9A variant in a neuropathy phenotype remains to be determined. ClinVar contains an entry for this variant (Variation ID: 430171). 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: Benign; 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.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001001938 SCV001159709 uncertain significance not specified 2019-06-26 criteria provided, single submitter clinical testing

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