Submissions for variant NM_000162.5(GCK):c.431T>C (p.Leu144Pro)

dbSNP: rs1554335596

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000523438	SCV000620363	uncertain significance	not provided	2017-08-25	criteria provided, single submitter	clinical testing	The L144P variant has been published previously in association with MODY; however, in one patient the variant was observed in a compound heterozygous state with another variant (Chambers et al., 2015; Bennett et al., 2015). The variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). L144P is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. In summary, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV002464024	SCV002605283	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 rs1554335596 in MODY, yet.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000523438	SCV004562480	uncertain significance	not provided	2023-08-31	criteria provided, single submitter	clinical testing	The GCK c.431T>C; p.Leu144Pro variant (rs1554335596) is reported in the literature in individuals affected with suspected maturity-onset diabetes of the young (MODY; Bennett 2015, Chambers 2015). This variant is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. Additionally, another variant at this codon (c.431_432delinsCT; p.Leu144Pro) has been reported in individuals with MODY (Toaima 2005). Computational analyses predict that the c.431T>C; p.Leu144Pro variant is deleterious (REVEL: 0.991). Due to limited information, the clinical significance of this variant is uncertain at this time. References: Bennett JT et al. Molecular genetic testing of patients with monogenic diabetes and hyperinsulinism. Mol Genet Metab. 2015 Mar;114(3):451-8. PMID: 25555642. Chambers C et al. Characteristics of maturity onset diabetes of the young in a large diabetes center. Pediatr Diabetes. 2016 Aug;17(5):360-7. PMID: 26059258. Toaima D et al. Identification of novel GCK and HNF1A/TCF1 mutations and polymorphisms in German families with maturity-onset diabetes of the young (MODY). Hum Mutat. 2005 May;25(5):503-4. PMID: 15841481.