Submissions for variant NM_198904.4(GABRG2):c.1217_1218del (p.Gln406fs)

dbSNP: rs1554101202

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000520177	SCV000620210	likely pathogenic	not provided	2017-08-23	criteria provided, single submitter	clinical testing	The c.1193_1194delAA variant in the GABRG2 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The c.1193_1194delAA variant causes a frameshift starting with codon Glutamine 398, changes this amino acid to an Arginine residue, and creates a premature Stop codon at position 4 of the new reading frame, denoted p.Gln398ArgfsX4. This variant is predicted to cause loss of normal protein function through protein truncation as the last 70 amino acids of the protein are lost and replaced with 3 incorrect amino acids. The c.1193_1194delAA variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). We interpret c.1193_1194delAA as a likely pathogenic variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001858007	SCV002234312	pathogenic	Epilepsy, childhood absence 2; Febrile seizures, familial, 8	2022-06-13	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the GABRG2 protein in which other variant(s) (p.Trp429*) have been determined to be pathogenic (PMID: 18566737). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 451497). This variant has not been reported in the literature in individuals affected with GABRG2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln398Argfs*4) in the GABRG2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 70 amino acid(s) of the GABRG2 protein.