ClinVar Miner

Submissions for variant NM_198904.4(GABRG2):c.1360C>T (p.Arg454Trp)

dbSNP: rs796052515
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000187538 SCV000241132 pathogenic not provided 2013-05-02 criteria provided, single submitter clinical testing p.Arg446Trp (CGG>TGG): c.1336 C>T in exon 9 of the GABRG2 gene (NM_000816.3) The Arg446Trp missense change has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The NHLBI ESP Exome Variant Project has not identified Arg446Trp in approximately 6,500 individuals of European or African American ethnicity, indicating that it is not a common benign variant in these populations. The amino acid substitution is non-conservative, as a positively charged, polar Arginine residue is replaced by an uncharged non-polar Tryptophan residue and multiple in-silico algorithms predict it may be damaging to the structure/function of the protein. However, while Arg446Trp alters a highly conserved position in the fourth transmembrane domain in the GABRG2 protein, other missense mutations have not been reported in this region of the protein. Therefore, based on the currently available information, Arg446Trp is interpreted as pathogenic. This variant has been observed de novo without verified parentage. The variant is found in INFANT-EPI panel(s).
Invitae RCV000645379 SCV000767124 uncertain significance Epilepsy, childhood absence 2; Febrile seizures, familial, 8 2023-08-24 criteria provided, single submitter clinical testing 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GABRG2 protein function. ClinVar contains an entry for this variant (Variation ID: 205556). This missense change has been observed in individual(s) with clinical features of GABRG2-related conditions (PMID: 29655203; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 446 of the GABRG2 protein (p.Arg446Trp).

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