ClinVar Genomic variation as it relates to human health
NM_000207.3(INS):c.265C>T (p.Arg89Cys)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic(3); Likely pathogenic(1); Uncertain significance(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000207.3(INS):c.265C>T (p.Arg89Cys)
Variation ID: 21117 Accession: VCV000021117.15
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11p15.5 11: 2159920 (GRCh38) [ NCBI UCSC ] 11: 2181150 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Apr 4, 2013 Feb 14, 2024 Jun 17, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000207.3:c.265C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000198.1:p.Arg89Cys missense NM_001042376.3:c.187+865C>T intron variant NM_001185097.2:c.265C>T NP_001172026.1:p.Arg89Cys missense NM_001185098.2:c.265C>T NP_001172027.1:p.Arg89Cys missense NM_001291897.2:c.265C>T NP_001278826.1:p.Arg89Cys missense NC_000011.10:g.2159920G>A NC_000011.9:g.2181150G>A NG_007114.1:g.6275C>T NG_050578.1:g.6290C>T P01308:p.Arg89Cys - Protein change
- R89C
- Other names
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- Canonical SPDI
- NC_000011.10:2159919:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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INS | No evidence available | No evidence available |
GRCh38 GRCh37 |
12 | 200 | |
INS-IGF2 | - | - | - |
GRCh38 GRCh37 |
- | 322 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (3) |
criteria provided, single submitter
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Mar 4, 2015 | RCV000020207.35 | |
Uncertain significance (2) |
criteria provided, single submitter
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- | RCV001089453.4 | |
Likely pathogenic (1) |
criteria provided, single submitter
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- | RCV002051790.2 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jun 17, 2023 | RCV002513137.3 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
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The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
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The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(Mar 04, 2015)
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criteria provided, single submitter
Method: clinical testing
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Diabetes mellitus, permanent neonatal
Affected status: yes
Allele origin:
germline
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Genetic Services Laboratory, University of Chicago
Accession: SCV000247611.1
First in ClinVar: Oct 05, 2015 Last updated: Oct 05, 2015 |
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Pathogenic
(Jun 17, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV003439674.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024 |
Comment:
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 … (more)
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. (less)
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Likely pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Neonatal diabetes mellitus
Affected status: yes
Allele origin:
germline
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Molecular Genetics, Madras Diabetes Research Foundation
Accession: SCV002318418.1
First in ClinVar: Apr 02, 2022 Last updated: Apr 02, 2022 |
Ethnicity/Population group: Indians
Geographic origin: India
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Pathogenic
(Mar 03, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV003837169.1
First in ClinVar: Mar 11, 2023 Last updated: Mar 11, 2023 |
Comment:
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 … (more)
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) (less)
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Uncertain significance
(-)
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criteria provided, single submitter
(K & H Uppaluri Personalized Medicine Clinic Variant Classification & Assertion Criteria_Updated V.1)
Method: research
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Diabetes mellitus, permanent neonatal 4
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
unknown
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Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic
Accession: SCV004190177.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
Comment:
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 … (more)
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) (less)
Comment on evidence:
However, more evidence is required to confer the association of this particular variant R89C/ rs80356669 with Permanent neonatal diabetes mellitus(PNDM)
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Pathogenic
(Jun 01, 2008)
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no assertion criteria provided
Method: literature only
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DIABETES MELLITUS, PERMANENT NEONATAL, 4
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000034567.3
First in ClinVar: Apr 04, 2013 Last updated: Dec 07, 2020 |
Comment on evidence:
In 2 unrelated probands with permanent neonatal diabetes mellitus (PNDM4; 618858), Stoy et al. (2007) identified heterozygosity for an arg89-to-cys (R89C) substitution in the INS … (more)
In 2 unrelated probands with permanent neonatal diabetes mellitus (PNDM4; 618858), Stoy et al. (2007) identified heterozygosity for an arg89-to-cys (R89C) substitution in the INS gene at the A-chain/C-peptide cleavage site, thus adding an additional unpaired cysteine residue at a solvent-exposed position in the molecule that is invariant among proinsulin sequences. In 2 unrelated mothers and sons and 2 other unrelated probands with PNDM, Edghill et al. (2008) identified heterozygosity for the R89C mutation in the INS gene. In 5 affected individuals from 2 families with PNDM, Polak et al. (2008) identified heterozygosity for R89C in the INS gene. The authors noted that one family ('family H') had diabetes that appeared to be nonautoimmune early-onset type 1 rather than bona fide neonatal diabetes, with diagnosis at 4 years of age in the mother and at 4.25 and 2.3 years of age in her son and daughter, respectively. Insulin requirements were relatively low for the patients in family H, and C-peptide levels were detectable, consistent with partially preserved beta-cell secretory function. In contrast, the mother in the other family ('family B') had poor metabolic control over the years and developed severe retinopathy, neuropathy, and macroangiopathy; at age 35 years, she underwent amputation of both feet. In 3 unrelated probands with PNDM who were known to be negative for mutations in the KCNJ11 gene (600937), Colombo et al. (2008) identified heterozygosity for an arg-to-cys substitution in the INS gene, which they designated R65C, located in the dibasic doublet between the C-peptide and the A-chain. Expression of the mutant proinsulin in HEK293 cells demonstrated defects in insulin protein folding and secretion. The mother of 1 patient and the father of another, who were also heterozygous for the mutation, had developed diabetes at 1 year and 4 years of age, respectively. C-peptide was initially detected in all 3 probands and was unexpectedly high in 1 of them; C-peptide declined to undetectable levels by the end of the study, supporting the hypothesis that postnatal failure to maintain beta-cell mass due to proteotoxic proinsulin misfolding is a primary cause of PNDM in patients with INS mutations. (less)
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not provided
(-)
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no classification provided
Method: not provided
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Permanent neonatal diabetes mellitus
Affected status: not provided
Allele origin:
not provided
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UniProtKB/Swiss-Prot
Accession: SCV000091158.1
First in ClinVar: Oct 31, 2013 Last updated: Oct 31, 2013 |
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not provided
(-)
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no classification provided
Method: literature only
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Permanent neonatal diabetes mellitus
Affected status: not provided
Allele origin:
unknown
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GeneReviews
Accession: SCV000040544.2
First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2022 |
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Insulin gene mutations linked to permanent neonatal diabetes mellitus in Indian population. | Gopi S | Journal of diabetes and its complications | 2021 | PMID: 34593315 |
Permanent Neonatal Diabetes Mellitus. | Adam MP | - | 2016 | PMID: 20301620 |
Identification of INS and KCNJ11 gene mutations in type 1B diabetes in Japanese children with onset of diabetes before 5 years of age. | Moritani M | Pediatric diabetes | 2013 | PMID: 22957706 |
Seven mutations in the human insulin gene linked to permanent neonatal/infancy-onset diabetes mellitus. | Colombo C | The Journal of clinical investigation | 2008 | PMID: 18451997 |
Heterozygous missense mutations in the insulin gene are linked to permanent diabetes appearing in the neonatal period or in early infancy: a report from the French ND (Neonatal Diabetes) Study Group. | Polak M | Diabetes | 2008 | PMID: 18171712 |
Insulin mutation screening in 1,044 patients with diabetes: mutations in the INS gene are a common cause of neonatal diabetes but a rare cause of diabetes diagnosed in childhood or adulthood. | Edghill EL | Diabetes | 2008 | PMID: 18162506 |
Insulin gene mutations as a cause of permanent neonatal diabetes. | Støy J | Proceedings of the National Academy of Sciences of the United States of America | 2007 | PMID: 17855560 |
Improved motor development and good long-term glycaemic control with sulfonylurea treatment in a patient with the syndrome of intermediate developmental delay, early-onset generalised epilepsy and neonatal diabetes associated with the V59M mutation in the KCNJ11 gene. | Slingerland AS | Diabetologia | 2006 | PMID: 17047922 |
Text-mined citations for rs80356669 ...
HelpRecord last updated Feb 20, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.