ClinVar Miner

Submissions for variant NM_198903.2(GABRG2):c.269C>T (p.Thr90Met) (rs1057520498)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000439122 SCV000515698 uncertain significance not provided 2016-12-30 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the GABRG2 gene. The T90M variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The T90M variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The T90M 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 occurs at a position that is conserved across species, and 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 GABRG2-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 benign variant.
Invitae RCV000688627 SCV000816249 likely pathogenic Epilepsy, childhood absence 2; Familial febrile seizures 8 2018-03-16 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 90 of the GABRG2 protein (p.Thr90Met). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to be de novo in an individual affected with seizures (Invitae). ClinVar contains an entry for this variant (Variation ID: 379114). 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: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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