ClinVar Miner

Submissions for variant NM_198904.4(GABRG2):c.670C>T (p.Arg224Ter)

dbSNP: rs1045493304
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000760614 SCV000890506 likely pathogenic not provided 2023-12-18 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect through slowing receptor deactivation, decreasing whole cell current compared to wild-type, and absent surface level expression of gamma2 subunit (PMID: 36979350); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 36979350)
Labcorp Genetics (formerly Invitae), Labcorp RCV001855929 SCV002180998 pathogenic Epilepsy, childhood absence 2; Febrile seizures, familial, 8 2023-04-07 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 620250). 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.Arg224*) in the GABRG2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GABRG2 are known to be pathogenic (PMID: 22539854, 22750526, 24407264).
Ambry Genetics RCV002360872 SCV002666739 pathogenic Inborn genetic diseases 2024-11-14 criteria provided, single submitter clinical testing The c.670C>T (p.R224*) alteration, located in exon 6 (coding exon 6) of the GABRG2 gene, consists of a C to T substitution at nucleotide position 670. This changes the amino acid from an arginine (R) to a stop codon at amino acid position 224. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant was reported in an individual with features consistent with GABRG2-related seizure disorders (Hernandez, 2023). Functional analysis demonstrated that the p.R224* variant altered GABAA receptor kinetics, function, and composition (Hernandez, 2023). Based on the available evidence, this alteration is classified as pathogenic.
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München RCV002468604 SCV002764717 likely pathogenic Febrile seizures, familial, 8 2021-09-06 criteria provided, single submitter clinical testing
Institute of Human Genetics, University of Leipzig Medical Center RCV002468604 SCV004027745 pathogenic Febrile seizures, familial, 8 2023-07-04 criteria provided, single submitter clinical testing Criteria applied: PVS1,PS4_MOD,PM2_SUP

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