Submissions for variant NM_000162.5(GCK):c.627GAT[3] (p.Met210_Ile211insMet)

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV002368789	SCV002660982	likely pathogenic	Maturity onset diabetes mellitus in young	2024-03-18	criteria provided, single submitter	clinical testing	The c.630_632dupGAT variant (also known as p.M210dup), located in coding exon 6 of the GCK gene, results from an in-frame duplication of GAT at nucleotide positions 630 to 632. This results in the duplication of an extra residue between codons 210 and 211. This alteration was detected in two unrelated families with maturity-onset diabetes of the young (MODY) (Sanyoura M et al. Diabetes Res Clin Pract, 2019 May;151:231-236; personal communication with Dr. Sanyoura). Based on internal structural analysis, the duplication is located in an allosteric site of glucokinase and is more deleterious than nearby pathogenic variants (Kamata K et al. Structure, 2004 Mar;12:429-38; Petit P et al. Acta Crystallogr D Biol Crystallogr, 2011 Nov;67:929-35). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003718532	SCV004509251	uncertain significance	not provided	2024-01-01	criteria provided, single submitter	clinical testing	This variant, c.630_632dup, results in the insertion of 1 amino acid(s) of the GCK protein (p.Met210dup), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with maturity-onset diabetes of the young (PMID: 31063852). ClinVar contains an entry for this variant (Variation ID: 1752729). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004690291	SCV005184542	uncertain significance	not specified	2024-05-28	criteria provided, single submitter	clinical testing	Variant summary: GCK c.630_632dupGAT (p.Met210dup) results in an in-frame duplication that is predicted to duplicate one amino acid into the encoded protein. The variant was absent in 251460 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.630_632dupGAT has been reported in the literature in individuals affected with Monogenic Diabetes (ex. Sanyoura_2019). This report does not provide unequivocal conclusions about association of the variant with Monogenic Diabetes. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 31063852). ClinVar contains an entry for this variant (Variation ID: 1752729). Based on the evidence outlined above, the variant was classified as uncertain significance.
GeneDx	RCV003718532	SCV005378557	uncertain significance	not provided	2024-04-15	criteria provided, single submitter	clinical testing	Identified in two families with MODY in published literature, however, detailed clinical information was not provided (PMID: 31063852); In-frame duplication of 1 amino acid in a non-repeat region; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31063852)