Submissions for variant NM_000162.5(GCK):c.1130G>A (p.Arg377His)

dbSNP: rs193922264

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Monogenic Diabetes Variant Curation Expert Panel	RCV003325945	SCV004032103	likely pathogenic	Monogenic diabetes	2023-08-08	reviewed by expert panel	curation	The c.1130G>A variant in the glucokinase gene, GCK, causes an amino acid change of arginine to histidine at codon 377 (p.(Arg377His)) of NM_000162.5. GCK is defined by the ClinGen MDEP VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.981, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in 4 unrelated individuals with hyperglycemia (PS4_Moderate; PMID 30155490, 17573900, internal lab contributors). This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and 3 generation family history of hyperglycemia) (PP4_Moderate; internal lab contributors). Another missense variant, c.1129C>T p.Arg377Cys, has been classified as pathogenic by the ClinGen MDEP VCEP but has a greater Grantham distance than p.Arg377His. Another missense variant, c.1129C>A p.Arg377Ser, has been classified as likely pathogenic by the ClinGen MDEP VCEP (PM5_Supporting). In summary, this variant meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.2.0, approved 6/7/2023) : PP2, PP3, PM2_Supporting, PS4_Moderate, PP4_Moderate, PM5_Supporting.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000029839	SCV000052494	likely pathogenic	Maturity-onset diabetes of the young type 2	2019-01-23	criteria provided, single submitter	clinical testing	Variant summary: GCK c.1130G>A (p.Arg377His) results in a non-conservative amino acid change located in the Hexokinase, C-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 231478 control chromosomes (gnomAD and publication) (ACMG PM2). c.1130G>A has been reported in the literature in at-least 5 affected individuals from diverse ethnicities (UK, Spain, China) diagnosed with MODY 2 (Huang_2018, Steele_2014, Estalella_2007). It reportedly co-segregated with diabetes in more than one affected family member in at-least one of the families ascertained (Estalella_2007). These data indicate that the variant is likely to be associated with disease (ACMG PS4). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites 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 two new reports indicating its presence in individuals diagnosed with MODY2 or a related diabetic phenotype have emerged since its original classification. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Athena Diagnostics Inc	RCV000518143	SCV000613397	uncertain significance	not specified	2017-03-22	criteria provided, single submitter	clinical testing
GeneDx	RCV001818186	SCV002064158	likely pathogenic	not provided	2022-01-17	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Missense variants in this gene are often considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 30155490, 24430320, 17573900, 34746319)
Ambry Genetics	RCV002321490	SCV002610155	uncertain significance	Maturity onset diabetes mellitus in young	2020-03-04	criteria provided, single submitter	clinical testing	The p.R377H variant (also known as c.1130G>A), located in coding exon 9 of the GCK gene, results from a G to A substitution at nucleotide position 1130. The arginine at codon 377 is replaced by histidine, an amino acid with highly similar properties. This variant was identified in two relatives from one family in which the proband had no autoantibodies and elevated fasting glucose, impaired glucose tolerance after oral glucose tolerance test, or diabetes during the first three decades of life (Estalella I et al. Clin. Endocrinol. (Oxf), 2007 Oct;67:538-46). It was also identified in cohorts of individuals with GCK variants; however, details were limited (Steele AM et al. JAMA, 2014 Jan;311:279-86; Huang X et al. J Diabetes Res, 2018 Aug;2018:7842064). 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 available evidence to date, the clinical significance of this alteration remains unclear.
Invitae	RCV001818186	SCV004295141	likely pathogenic	not provided	2023-11-17	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 377 of the GCK protein (p.Arg377His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of autosomal dominant maturity-onset diabetes of the young and/or GCK-related conditions and/or GCK-related conditions (PMID: 17573900, 24430320, 30155490, 34746319). ClinVar contains an entry for this variant (Variation ID: 36176). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GCK protein function with a positive predictive value of 80%. This variant disrupts the p.Arg377 amino acid residue in GCK. Other variant(s) that disrupt this residue have been observed in individuals with GCK-related conditions (PMID: 17573900, 19790256, 34746319), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.