Submissions for variant NM_000162.5(GCK):c.566T>C (p.Ile189Thr)

dbSNP: rs1554335441

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Monogenic Diabetes Variant Curation Expert Panel	RCV003228938	SCV003926585	pathogenic	Monogenic diabetes	2023-05-08	reviewed by expert panel	curation	The c.566T>C variant in the glucokinase gene, GCK, causes an amino acid change of isoleucine to threonine at codon 189 (p.Ile189Thr) of NM_000162.5. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.969, which is greater than the MDEP VCEP threshold of 0.70 (PP3) and is absent from gnomAD v2.1.1 (PM2_Supporting). 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 was identified in 7 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; internal lab contributors). Additionally, this variant was identified in at least one individual with a clinical history highly specific for GCK-MODY (fasting glucose = 125 mg/dl and HbA1c = 6.5%) (PP4, internal lab contributors). Lastly, this variant segregated with diabetes, with five informative meioses in two families with MODY (PP1_Strong; internal lab contributors). In summary, c.566T>C meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1.0, approved 3/23/2023): PM2_Supporting, PP3, PP2, PP4, PP1_Strong, PS4.
GeneDx	RCV000498428	SCV000589596	uncertain significance	not provided	2020-05-06	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 19790256)
Geisinger Clinic, Geisinger Health System	RCV002285343	SCV002562180	pathogenic	Maturity-onset diabetes of the young type 2	2022-08-02	criteria provided, single submitter	research	PM2, PP3, PP2, PS4, PP4_Moderate, PP1_Strong
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV002350106	SCV002605205	likely 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 rs1554335441 in MODY, yet.
Ambry Genetics	RCV002350106	SCV002647799	likely pathogenic	Maturity onset diabetes mellitus in young	2021-03-26	criteria provided, single submitter	clinical testing	The p.I189T variant (also known as c.566T>C), located in coding exon 5 of the GCK gene, results from a T to C substitution at nucleotide position 566. The isoleucine at codon 189 is replaced by threonine, an amino acid with similar properties. This variant has been detected in multiple unrelated individuals with maturity-onset diabetes of the young (Osbak KK et al. Hum Mutat, 2009 Nov;30:1512-26; Ambry internal data). Based on internal structural analysis, this alteration results in local structural destabilization (Petit P et al. Acta Crystallogr D Biol Crystallogr, 2011 Nov;67:929-35). This variant was not reported in population-based 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.
PreventionGenetics, part of Exact Sciences	RCV003403149	SCV004104273	likely pathogenic	GCK-related condition	2023-05-05	criteria provided, single submitter	clinical testing	The GCK c.566T>C variant is predicted to result in the amino acid substitution p.Ile189Thr. This variant was reported in one family with maturity onset diabetes of the young (Table S1, Osbak et al. 2009. PubMed ID: 19790256). Additional information on the carrier(s) of this variant was not provided. This variant was also detected in a patient with biochemical markers and a strong family history suggestive of autosomal dominant maturity onset diabetes (Internal data, PreventionGenetics). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Another missense substitution affecting this amino acid has been reported in two patients with MODY (Yalçıntepe et al. 2021. PubMed ID: 33565752). We interpret this variant as likely pathogenic.