ClinVar Miner

Submissions for variant NM_000162.5(GCK):c.1141_1142del (p.Met381fs)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV002456979 SCV002614349 pathogenic Maturity onset diabetes mellitus in young 2021-01-14 criteria provided, single submitter clinical testing The c.1141_1142delAT pathogenic mutation, located in coding exon 9 of the GCK gene, results from a deletion of two nucleotides at nucleotide positions 1141 to 1142, causing a translational frameshift with a predicted alternate stop codon (p.M381Vfs*77). This mutation was identified in one maturity-onset diabetes of the young family; however, clinical details were limited (Osbak KK et al. Hum Mutat, 2009 Nov;30:1512-26). This alteration occurs at the 3' terminus of theGCK gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 86 amino acids of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). As such, this alteration is interpreted as a disease-causing mutation.
Labcorp Genetics (formerly Invitae), Labcorp RCV003560948 SCV004295138 pathogenic not provided 2023-04-12 criteria provided, single submitter clinical testing This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Met381Valfs*77) in the GCK gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 85 amino acid(s) of the GCK protein. This premature translational stop signal has been observed in individual(s) with clinical features of GCK-related conditions (PMID: 19790256). For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the GCK protein in which other variant(s) (p.Ala456Val) have been determined to be pathogenic (PMID: 11916951, 14687251). 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: 1731302).

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