ClinVar Miner

Submissions for variant NM_001365536.1(SCN9A):c.2085A>G (p.Ile695Met) (rs199588089)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000727145 SCV000293492 uncertain significance not provided 2016-03-28 criteria provided, single submitter clinical testing The I684M variant has not been published in association with an inherited pain syndrome, to our knowledge. It was previously reported to be maternally inherited in a patient with Dravet syndrome who harbored a de novo pathogenic variant in the SCN1A gene that explained the phenotype, and the I684M variant in SCN9A was suggested to act as a modifier of the Dravet syndrome phenotype; however, further research is needed to clarify the possible association between SCN9A variants and seizure predisposition (Singh et al., 2009). The I684M variant was not observed with any significant frequency in the Exome Aggregation Consortium (ExAC) data set, indicating it is not a common benign variant. It is a conservative amino acid substitution that occurs at a position in the cytoplasmic loop between the first and second transmembrane domain, and amino acids with similar properties to Isoleucine are tolerated across species at that position. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000727145 SCV000706131 uncertain significance not provided 2017-02-20 criteria provided, single submitter clinical testing
Invitae RCV000647766 SCV000769569 uncertain significance Hereditary sensory and autonomic neuropathy type IIA; Generalized epilepsy with febrile seizures plus, type 7 2020-05-31 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with methionine at codon 684 of the SCN9A protein (p.Ile684Met). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and methionine. This variant is present in population databases (rs199588089, ExAC 0.01%). This variant has been reported in an individual affected with Dravet syndrome. This individual also carried a de novo, pathogenic variant in the SCN1A gene. (PMID: 19763161). ClinVar contains an entry for this variant (Variation ID: 246106). 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 tolerated, 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.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000727145 SCV001152535 uncertain significance not provided 2019-03-01 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001286825 SCV001473444 uncertain significance none provided 2020-02-03 criteria provided, single submitter clinical testing

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