ClinVar Miner

Submissions for variant NM_000162.5(GCK):c.483+2T>C

dbSNP: rs1554335564
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000579201 SCV000680715 pathogenic not provided 2017-12-13 criteria provided, single submitter clinical testing The c.483+2 T>C splice site variant has been previously reported in association with MODY, including as a de novo ocurrence (Osbak et al., 2009; de Santana et al., 2017). This variant destroys the canonical splice donor site in intron 4, and is expected to cause abnormal gene splicing. The variant is not observed in large population cohorts (Lek et al., 2016). In summary, we consider this variant to be pathogenic.
Geisinger Clinic, Geisinger Health System RCV002285369 SCV002562175 pathogenic Maturity-onset diabetes of the young type 2 2022-08-02 criteria provided, single submitter research PVS1, PM2, PP3, PP4, PS4_Supporting
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic RCV002464026 SCV002605240 likely pathogenic Maturity onset diabetes mellitus in young criteria provided, single submitter research Potent mutations in GCK gene is associated with poor secretion of insulin. Its associated with milder forms of diabetes, which can be controlled by diet . However, there is no sufficient evidence to ascertain the significance of rs1554335564 in MODY, yet.
Labcorp Genetics (formerly Invitae), Labcorp RCV000579201 SCV004295176 pathogenic not provided 2024-01-19 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 4 of the GCK gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in GCK are known to be pathogenic (PMID: 7553875, 9867845, 14578306, 24323243, 25015100). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with maturity-onset diabetes of the young (PMID: 19790256, 29510678, 35472491). ClinVar contains an entry for this variant (Variation ID: 488812). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.

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