ClinVar Miner

Submissions for variant NM_198903.2(GABRG2):c.1207C>T (p.Arg403Trp) (rs374512652)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000187534 SCV000241128 uncertain significance not provided 2017-08-09 criteria provided, single submitter clinical testing p.Arg363Trp (CGG>TGG):c.1087 C>T in exon 8 of the GABRG2 gene (NM_000816.3) The R363W variant has been reported previously in an unaffected control individual; however, additional information regarding the variant or the phenotype of the individual was not reported (Reinthaler et al., 2015). A different amino acid substitution at this position (R363Q) has been reported in an individual with generalized epilepsy with febrile seizures plus (GEFS+); however, additional clinical information was not provided, and parental studies were not performed (Cantarín-Extremera et al. 2011). The R363W variant is observed in 2/10406 (0.2%) alleles from individuals of African background (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R363W 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 in mammals, and in silico analysis predicts this variant is probably 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.
Ambry Genetics RCV000720807 SCV000851691 uncertain significance Seizures 2017-05-23 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Invitae RCV000795577 SCV000935045 uncertain significance Epilepsy, childhood absence 2; Familial febrile seizures 8 2018-08-31 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 363 of the GABRG2 protein (p.Arg363Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs374512652, ExAC 0.02%). This variant has not been reported in the literature in individuals with GABRG2-related disease. ClinVar contains an entry for this variant (Variation ID: 205552). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). 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.

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