Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000516927 | SCV000052539 | uncertain significance | not specified | 2019-02-04 | criteria provided, single submitter | clinical testing | Variant summary: The variant, GCK c.457C>T (p.Pro153Ser) results in a non-conservative amino acid change located in the Hexokinase, N-terminal domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function consistent with an ExAC z score of 4.39 indicative of a gene relatively intolerant to benign missense variation (ACMG PP3, PP2). The variant was absent in 246268 control chromosomes (gnomAD) (ACMG PM2). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.457C>T has been reported in the literature in an individual affected with Maturity Onset Diabetes of the Young 2/Neonatal Diabetes Mellitus (Aloi_2017). However, this data does not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. This variant was previously classified as a VUS-possibly pathogenic variant that was converted during ClinVar submission to likely pathogenic in 2011. As summarized above, at-least one new report indicating its presence in an individual diagnosed with MODY or a related diabetic phenotype have emerged since its original classification. Based on the evidence outlined above, until unequivocal co-segregation with disease in additional families/individuals with MODY2/NDM and functional studies corroborating the evidence described above is obtained, the variant was conservatively classified as uncertain significance. |
| Athena Diagnostics Inc | RCV000991335 | SCV000613430 | uncertain significance | not provided | 2019-04-25 | criteria provided, single submitter | clinical testing | |
| Ambry Genetics | RCV002336092 | SCV002638563 | likely pathogenic | Maturity onset diabetes mellitus in young | 2022-05-24 | criteria provided, single submitter | clinical testing | The p.P153S variant (also known as c.457C>T), located in coding exon 4 of the GCK gene, results from a C to T substitution at nucleotide position 457. The proline at codon 153 is replaced by serine, an amino acid with similar properties. This variant was detected in one individual from a cohort of 3781 consecutive patients diagnosed with diabetes or impaired fasting glucose (<18 years) with negative type 1 diabetes antibodies (Delvecchio M et al. J. Clin. Endocrinol. Metab., 2017 06;102:1826-1834) and was later reported to segregate with disease in an Italian family in which the proband was diagnosed with impaired fasting glucose at 5 years of age and was described as having normal glucose tolerance, HbA1C of 6.5%, normal BMI and mother with gestational diabetes (Aloi C et al. Acta Diabetol, 2017 Oct;54:913-923). Based on internal structural analysis, this variant is anticipated to disrupt a region of known function and is more disruptive than nearby pathogenic variants (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. Based on the majority of available evidence to date, this variant is likely to be pathogenic. |