ClinVar Miner

Submissions for variant NM_000824.5(GLRB):c.1414C>T (p.Arg472Ter)

dbSNP: rs570886685
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV002777267 SCV003576609 uncertain significance Inborn genetic diseases 2021-11-03 criteria provided, single submitter clinical testing The c.1414C>T (p.R472*) alteration, located in exon 10 (coding exon 9) of the GLRB gene, consists of a C to T substitution at nucleotide position 1414. This changes the amino acid from a arginine (R) to a stop codon at amino acid position 472. Premature stop codons are typically deleterious in nature (Richards, 2015). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp RCV003530277 SCV004292764 likely pathogenic Hyperekplexia 2 2024-12-17 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg472*) in the GLRB gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 26 amino acid(s) of the GLRB protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with hyperekplexia (PMID: 23184146; internal data). This variant is also known as R450X. ClinVar contains an entry for this variant (Variation ID: 2252581). This variant disrupts a region of the GLRB protein in which other variant(s) (p.Tyr492Cys) have been observed in individuals with GLRB-related conditions (PMID: 23184146). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Breakthrough Genomics, Breakthrough Genomics RCV003530277 SCV005088824 likely pathogenic Hyperekplexia 2 2020-04-03 criteria provided, single submitter clinical testing This variant (also known as, c.G1415A; p.R450X) was previously reported in a patient of Jordan origin diagnosed with hyperekplexia in homozygous state. Functional analysis of the variant in the same study suggested that the variant has reduced cell-surface protein expression compared with wild type [PMID: 23184146].

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