Submissions for variant NM_000207.3(INS):c.265C>T (p.Arg89Cys)

dbSNP: rs80356669

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000020207	SCV000247611	pathogenic	Permanent neonatal diabetes mellitus	2015-03-04	criteria provided, single submitter	clinical testing
Molecular Genetics, Madras Diabetes Research Foundation	RCV002051790	SCV002318418	likely pathogenic	Neonatal diabetes mellitus		criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV002513137	SCV003439674	pathogenic	not provided	2023-06-17	criteria provided, single submitter	clinical testing	This missense change has been observed in individual(s) with autosomal dominant neonatal diabetes (PMID: 17855560, 22957706). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 89 of the INS protein (p.Arg89Cys). ClinVar contains an entry for this variant (Variation ID: 21117). For these reasons, this variant has been classified as Pathogenic. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive.
GeneDx	RCV002513137	SCV003837169	pathogenic	not provided	2023-03-03	criteria provided, single submitter	clinical testing	Published in vitro functional studies suggest a negative effect on subcellular insulin localization and incomplete processing of proinsulin to insulin, but no inhibition of wildtype insulin secretion (Rajan et al., 2010); Not observed in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 28597946, 23074673, 23771172, 18162506, 20034470, 22957706, 17855560, 19900242, 28667717, 23050777, 25555642, 18171712, 28323911, 31605659, 35518939, 34593315, 32792356, 19952343)
OMIM	RCV001089453	SCV000034567	pathogenic	Diabetes mellitus, permanent neonatal 4	2008-06-01	no assertion criteria provided	literature only
GeneReviews	RCV000020207	SCV000040544	not provided	Permanent neonatal diabetes mellitus		no assertion provided	literature only
UniProtKB/Swiss-Prot	RCV000020207	SCV000091158	not provided	Permanent neonatal diabetes mellitus		no assertion provided	not provided
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV001089453	SCV004190177	uncertain significance	Diabetes mellitus, permanent neonatal 4		flagged submission	research	Potent mutations in INS gene can cause early onset diabetes mellitus which is insulin dependent. May have poor response to sulfonylureas, as potent mutations in this gene can cause beta cell destruction.However, more evidence is required to confer the association of this particular variant R89C/ rs80356669 with Permanent neonatal diabetes mellitus(PNDM)
PreventionGenetics, part of Exact Sciences	RCV004730851	SCV005340022	pathogenic	INS-related disorder	2024-05-10	no assertion criteria provided	clinical testing	The INS c.265C>T variant is predicted to result in the amino acid substitution p.Arg89Cys. This variant, also known as p.Arg65Cys using legacy nomenclature, has been reported in several individuals, often occurring de novo, with permanent neonatal diabetes (Støy et al. 2007. PubMed ID: 17855560; Moritani et al. 2012. PubMed ID: 22957706; Fu et al. 2019. PubMed ID: 31605659; Lin Y et al 2020. PubMed ID: 32792356; Globa et al. 2022. PubMed ID: 36398453). In vitro studies demonstrate that expression of this variant results in aberrant processing of proinsulin to insulin and retainment in the endoplasmic reticulum (Rajan et al. 2009. PubMed ID: 19952343; Park et al. 2009. PubMed ID: 20034470). This variant has not been reported in a large population database, indicating this variant is rare. Additionally, different missense changes impacting the same amino acid (p.Arg89Pro, p.Arg89His, and p.Arg89Leu) have also been reported in association with hyperproinsulinemia and diabetes (Robbins et al. 1984. PubMed ID: 6368587; Billings et al. 2022. PubMed ID: 36208030). Taken together, the c.265C>T (p.Arg89Cys) variant is interpreted as pathogenic.