Submissions for variant NM_000207.3(INS):c.94G>A (p.Gly32Ser)

dbSNP: rs80356664

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000117279	SCV000151453	pathogenic	Type 1 diabetes mellitus 2	2013-11-04	criteria provided, single submitter	clinical testing
GeneDx	RCV001775542	SCV002013056	pathogenic	not provided	2024-06-27	criteria provided, single submitter	clinical testing	Published functional studies suggest a damaging effect on protein function (PMID: 20034470); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 17855560, 18162506, 19900242, 27634015, 31365591, 31605659, 18840770, 19952343, 26530398, 31264968, 32792356, 32041611, 37897565, 37048081, 36398453, 36151994, 36504295, 36724370, 36418577, 34387403, 38793013, 36655002, 35518939, 20034470)
Molecular Genetics, Madras Diabetes Research Foundation	RCV000030072	SCV002318416	likely pathogenic	Neonatal diabetes mellitus		criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001775542	SCV004294055	pathogenic	not provided	2023-12-30	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 32 of the INS protein (p.Gly32Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant permanent neonatal diabetes mellitus (PMID: 17855560). 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. ClinVar contains an entry for this variant (Variation ID: 21122). 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. Experimental studies have shown that this missense change affects INS function (PMID: 19952343). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000020212	SCV004848570	pathogenic	Permanent neonatal diabetes mellitus	2021-07-21	criteria provided, single submitter	clinical testing	The p.Gly32Ser variant in INS has been reported in at least 15 individuals with early-onset or infantile diabetes, including 8 de novo occurrences, and segregated with disease in 4 affected individuals from 1 family (Stoy 2007 PMID:17855560, Edghill 2008 PMID: 18162506, Bonfanti 2009 PMID: 18840770, Rubio-Cabezas 2009 PMID: 19900242, Jahnavi 2013 PMID: 22831748, Globa 2015 PMID: 26208381, Ortolani 2015 PMID: 26239141, Brahm 2016 PMID: 27634015, Wasserman 2016 PMID: 26530398, Urrutia 2019 PMID: 31365591, Fu 2020 PMID: 31605659, Lin 2020 PMID: 32792356). It was absent from large population studies but has been reported in ClinVar (Variation ID 21122). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In vitro functional studies support an impact on protein function (Park 2010 PMID: 20034470, Rajan 2010 PMID: 19952343). Animal models in mice support that this variant causes diabetes (Austin 2020 PMID: 32994272). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant monogenic diabetes. ACMG/AMP Criteria applied: PS4, PM6_Strong, PM2_Supporting, PS3_Moderate, PP1, PP3.
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV001089451	SCV005418588	pathogenic	Diabetes mellitus, permanent neonatal 4		criteria provided, single submitter	clinical testing	PM2_Supporting+PS4_Moderate+PS2+PP4+PP3_Strong
OMIM	RCV001089451	SCV000034565	pathogenic	Diabetes mellitus, permanent neonatal 4	2007-09-18	no assertion criteria provided	literature only
GeneReviews	RCV000020212	SCV000040549	not provided	Permanent neonatal diabetes mellitus		no assertion provided	literature only
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000030072	SCV000052727	not provided	Neonatal diabetes mellitus	2015-04-03	no assertion provided	clinical testing
UniProtKB/Swiss-Prot	RCV000020212	SCV000091167	not provided	Permanent neonatal diabetes mellitus		no assertion provided	not provided
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV001089451	SCV004174201	uncertain significance	Diabetes mellitus, permanent neonatal 4		flagged submission	research	Potent mutations in the INS gene can cause early onset diabetes mellitus which is insulin dependent. May have poor response to sulfonylureas, mutations in this gene can cause beta cell destruction.Sufficient evidence is found to confer the association of this particular variant G32S/rs80356664 with Neonatal diabetes.