Submissions for variant NM_198904.4(GABRG2):c.1277_1278insTTTTTTTTTTTTTTTTTTTTNNNNNNNNNNTTTTTTTTTTTTTTCTTTTTTTTTTTATTTTTTTATTTTTTTTTTTTTTTTTATTATACTCTAAGTTTTAGGGTACATGTGCCAGTTTTTT (p.Phe426_Cys427insPhePhePhePhePhePheXaaXaaXaaXaaPhePhePhePheSerPhePhePheTyrPhePheIlePhePhePhePhePheIleIleLeuTer)

Total submissions: 1

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003011658	SCV003306300	pathogenic	Epilepsy, childhood absence 2; Febrile seizures, familial, 8	2022-09-19	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Retrotransposon insertions including LINE1 (L1), Alu, and SVA (SINE-VNTR-Alu) have been reported to disrupt protein function (PMID: 19763152, 20307669, 22406018). However the effect of this particular variant is unknown. This variant disrupts a region of the GABRG2 protein in which other variant(s) (p.Arg437Leu) have been determined to be pathogenic (Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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 inserts a large fragment of DNA, likely a transposable element, in exon 9 of the GABRG2 gene (c.1253_1254ins121), causing a frameshift at codon 419 (p.Cys419Phefs*31). The exact size and sequence of the insertion cannot be determined by the current assay. However, the insertion is expected to result in an absent or disrupted protein product.