Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000657902 | SCV000779667 | uncertain significance | not provided | 2018-05-21 | criteria provided, single submitter | clinical testing | The N180K variant has been reported in a patient with gestational diabetes, persisting fasting hyperglycemia, and a family history of glucose tolerance issues (Ellard et al., 2000). A different nucleotide change (T>C rather than T>G) resulting in the same amino acid substitution has also been reported in a patient with GCK-MODY (Gozlan et al., 2012). The N180K variant is not observed in large population cohorts (Lek et al., 2016). The N180K variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. This variant occurs in a variant hotspot for the GCK gene and missense variants in nearby residues (E177D, G178R/W/E/V, V181A, V182M) have been reported in the Human Gene Mutation Database in association with GCK-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. In summary, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. |
| Athena Diagnostics Inc | RCV000657902 | SCV001144020 | likely pathogenic | not provided | 2019-04-10 | criteria provided, single submitter | clinical testing | Not found in the total gnomAD dataset, and the data is high quality (0/282448 chr). Statistically enriched in patients compared to ethnically matched controls. Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. |
| Ambry Genetics | RCV002343405 | SCV002650509 | likely pathogenic | Maturity onset diabetes mellitus in young | 2016-12-23 | criteria provided, single submitter | clinical testing | The p.N180K variant (also known as c.540T>G), located in coding exon 5 of the GCK gene, results from a T to G substitution at nucleotide position 540. The asparagine at codon 180 is replaced by lysine, an amino acid with similar properties. In a small study (n = 15) of women with a history of gestational diabetes (GDM), persistent fasting hyperclycemia outside of pregnancy (diet controlled), and a first degree relative with either elevated fasting glucose or a history of type II or GDMs, one individual was identified to be heterozygous for this variant; two of her relatives with elevated fasting plasma glucose were also heterozygous (Ellard S et al. Diabetologia, 2000 Feb;43:250-3). In another study, a 3 year old female with a clinical diagnosis of MODY, and her mother with a history of GDM, each carried the p.N180K alteration (Gozlan Y et al. Pediatr Diabetes, 2012 Sep;13:e14-21). This variant was not reported in the ExAC database, with coverage at this position. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic. |