Submissions for variant NM_000162.5(GCK):c.364-1G>A

dbSNP: rs1057521094

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000429688	SCV000521047	likely pathogenic	not provided	2016-10-05	criteria provided, single submitter	clinical testing	The c.364-1 G>A splice site variant in the GCK gene has been previously reported in a patient with incidental hyperglycemia (Lorini et al., 2009). This variant destroys the canonical splice acceptor site in intron 3, and is expected to cause abnormal gene splicing. However, the adjacent exon 4 is predicted to remain in frame. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown. Additionally, the variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Therefore, we consider this variant to be likely pathogenic.
Athena Diagnostics Inc	RCV000429688	SCV000613424	pathogenic	not provided	2021-04-29	criteria provided, single submitter	clinical testing	This variant is expected to severely impact normal RNA splicing, and consequently, protein structure and/or function. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with clinical features associated with this gene.
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV002450985	SCV002605275	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 rs1057521094 in MODY, yet.
Ambry Genetics	RCV002450985	SCV002613759	pathogenic	Maturity onset diabetes mellitus in young	2017-05-17	criteria provided, single submitter	clinical testing	The c.364-1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide upstream from coding exon 4 of the GCK gene. This variant was identified in multiple families with maturity-onset diabetes of the young (Osbak KK et al. Hum. Mutat., 2009 Nov;30:1512-26). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic.