Submissions for variant NM_000207.3(INS):c.25C>T (p.Pro9Ser)

gnomAD frequency: 0.00001  dbSNP: rs372122432

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000325720	SCV000369893	uncertain significance	Maturity-onset diabetes of the young type 10	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV000389656	SCV000369894	uncertain significance	Transient Neonatal Diabetes, Dominant/Recessive	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV002464166	SCV002605410	uncertain significance	Neonatal insulin-dependent diabetes mellitus		criteria provided, single submitter	research	Mutations in INS gene can cause early onset diabetes mellitus which is insulin dependent. May have poor response to sulfonylureas, as this mutation can cause beta cell destruction. However no sufficient evidence is found to ascertain the role of this particular variant rs372122432, yet.
New York Genome Center	RCV002467727	SCV002764585	uncertain significance	Type 1 diabetes mellitus 2; Maturity-onset diabetes of the young type 10; Hyperproinsulinemia; Diabetes mellitus, permanent neonatal 4	2021-02-22	criteria provided, single submitter	clinical testing	The heterozygous c.25C>T (p.Pro9Ser) missense variant identified in the INS gene is not reported in affected individuals in the literature. The variant has been reported in ClinVar as a variant of uncertain significance (Variation ID:304058). A different missense variant (p.Pro9Arg)affecting the same residue has been reported de novo in infants affected with neonatal diabetes mellitus [PMID:31196892, 31019026]. The p.Pro9Ser variant identified in this individual has 0.00001314 allele frequency in the gnomAD(V3) database (2 out of 152,230 heterozygous alleles, no homozygotes) suggesting it is not a common benign variant in populations represented in that database. The affected residue is weakly conserved and in silico tools provide conflicting predictions about potential pathogenicity of this variant [CADD score = 20.8, REVEL score = 0.428]. Based on the available evidence, the heterozygous c.25C>T (p.Pro9Ser)missense variant identified in the INS gene is reported as a variant of uncertain significance.
Fulgent Genetics, Fulgent Genetics	RCV002467727	SCV002784064	uncertain significance	Type 1 diabetes mellitus 2; Maturity-onset diabetes of the young type 10; Hyperproinsulinemia; Diabetes mellitus, permanent neonatal 4	2022-03-19	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003417983	SCV004116499	uncertain significance	INS-related disorder	2022-11-15	criteria provided, single submitter	clinical testing	The INS c.25C>T variant is predicted to result in the amino acid substitution p.Pro9Ser. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.