Submissions for variant NM_000162.5(GCK):c.1327G>T (p.Glu443Ter)

dbSNP: rs1562711915

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Monogenic Diabetes Variant Curation Expert Panel	RCV001844229	SCV004032112	pathogenic	Monogenic diabetes	2023-09-01	reviewed by expert panel	curation	The c.1327G>T variant in the glucokinase gene, GCK causes a premature stop codon in the protein at codon 443 (NM_000162.5). While this variant, located in exon 10 of 10, is predicted to cause a premature stop codon and to escape nonsense mediated decay, it is in a functionally important region of a gene where loss-of-function is an established disease mechanism (PVS1; PMID:19790256). This variant was identified in 4 unrelated individuals with a clinical picture consistent with monogenic diabetes (PS4_Moderate; PMID: 20337973, PMID: 32901087, ClinVar ID 585915), including at least one individual with a clinical history suggestive of GCK-MODY but with insufficient clinical information provided to evaluate for PP4. In summary, c.1327G>T meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PVS1, PS4_Moderate, PM2_Supporting.
Athena Diagnostics	RCV000711766	SCV000842160	pathogenic	not provided	2018-01-03	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001844229	SCV002103382	pathogenic	Monogenic diabetes	2023-11-03	criteria provided, single submitter	clinical testing	Variant summary: GCK c.1327G>T (p.Glu443X) results in a premature termination codon and is not predicted to cause nonsense mediated decay, but is expected to result in a truncation of the encoded protein, a commonly known mechanism for disease. Variants downstream of this position have been classified as pathogenic by our laboratory and others in ClinVar. The variant was absent in 242994 control chromosomes (gnomAD). To our knowledge, no occurrence of c.1327G>T in individuals affected with Monogenic Diabetes and no experimental evidence demonstrating its impact on protein function have been reported in the literature. Two submitters, including the ClinGen Monogenic Diabetes Variant Curation Expert Panel, have cited clinical-significance assessments for this variant to ClinVar after 2014. Both submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV002463729	SCV002605050	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 rs1562711915 in MODY, yet.
GeneDx	RCV000711766	SCV005421401	likely pathogenic	not provided	2024-06-04	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation, as the last 23 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 20337973, 32901087, 19790256)