Submissions for variant NM_000162.5(GCK):c.630G>T (p.Met210Ile)

dbSNP: rs193922313

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Monogenic Diabetes Variant Curation Expert Panel	RCV003318496	SCV004022340	pathogenic	Monogenic diabetes	2024-01-22	reviewed by expert panel	curation	The c.630G>T variant in the glucokinase gene, GCK, causes an amino acid change of methionine to isoleucine at codon 210 (p.(Met210Ile)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.9399, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent in gnomAD v2.1.1 (PM2_Supporting), and was identified in an individual with diabetes; however, PP4 is unable to be evaluated due to lack of clinical information (ClinVar ID 36236). Two other missense variants, c.629T>A (p.Met210Lys) and c.629T>C (p.Met210Thr), have been classified as pathogenic by the ClinGen MDEP (PM5_Strong). The nucleotide change c.630G>A, which causes the same amino acid change, has been classified as pathogenic for monogenic diabetes by the ClinGen MDEP (PS1). Taken together, the c.630G>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): PM5_Strong, PS1, PP2, PP3, PM2_Supporting.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000029899	SCV000052554	likely pathogenic	Maturity-onset diabetes of the young type 2	2011-08-18	criteria provided, single submitter	curation	Converted during submission to Likely pathogenic.
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV002362597	SCV002605192	uncertain risk allele	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 rs193922313 in MODY, yet.
Ambry Genetics	RCV002362597	SCV002660597	uncertain significance	Maturity onset diabetes mellitus in young	2016-02-16	criteria provided, single submitter	clinical testing	The p.M210I variant (also known as c.630G>T), located in coding exon 6 of the GCK gene, results from a G to T substitution at nucleotide position 630. The methionine at codon 210 is replaced by isoleucine, an amino acid with highly similar properties. Other alterations at the same amino acid position (p.M210K and p.M210T) have been reported in affected individuals including at least one homozygous individual who was reported to have permanent neonatal diabetes (Njolstad et al. N Engl J Med. 2001;344: 1588-92, Velho et al. Diabetologia. 1997;40: 217-24). The p.M210I variant was previously reported in the SNPDatabase as rs193922313. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.