ClinVar Genomic variation as it relates to human health
NM_000207.3(INS):c.94G>A (p.Gly32Ser)
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000207.3(INS):c.94G>A (p.Gly32Ser)
Variation ID: 21122 Accession: VCV000021122.17
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11p15.5 11: 2160878 (GRCh38) [ NCBI UCSC ] 11: 2182108 (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 Sep 16, 2024 Jun 27, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000207.3:c.94G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000198.1:p.Gly32Ser missense NM_001042376.3:c.94G>A NP_001035835.1:p.Gly32Ser missense NM_001185097.2:c.94G>A NP_001172026.1:p.Gly32Ser missense NM_001185098.2:c.94G>A NP_001172027.1:p.Gly32Ser missense NM_001291897.2:c.94G>A NP_001278826.1:p.Gly32Ser missense NR_003512.4:n.153G>A non-coding transcript variant NC_000011.10:g.2160878C>T NC_000011.9:g.2182108C>T NG_007114.1:g.5317G>A NG_050578.1:g.5332G>A P01308:p.Gly32Ser - Protein change
- G32S
- Other names
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- Canonical SPDI
- NC_000011.10:2160877:C:T
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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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Trans-Omics for Precision Medicine (TOPMed) 0.00000
- Links
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
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
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
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 | 202 | |
INS-IGF2 | - | - | - |
GRCh38 GRCh37 |
- | 330 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
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
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
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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Jul 21, 2021 | RCV000020212.32 | |
Likely pathogenic (2) |
criteria provided, single submitter
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- | RCV000030072.4 | |
Pathogenic (1) |
criteria provided, single submitter
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Nov 4, 2013 | RCV000117279.6 | |
Pathogenic (2) |
no assertion criteria provided
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Sep 18, 2007 | RCV001089451.5 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jun 27, 2024 | RCV001775542.6 |
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
Help
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
Help
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
(Nov 04, 2013)
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criteria provided, single submitter
Method: clinical testing
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Diabetes mellitus, insulin-dependent, 2
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Genetic Services Laboratory, University of Chicago
Accession: SCV000151453.1
First in ClinVar: May 17, 2014 Last updated: May 17, 2014 |
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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: SCV002318416.1
First in ClinVar: Apr 02, 2022 Last updated: Apr 02, 2022 |
Ethnicity/Population group: Indians
Geographic origin: India
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Pathogenic
(Dec 30, 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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV004294055.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
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). … (more)
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. (less)
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Pathogenic
(Jul 21, 2021)
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criteria provided, single submitter
Method: clinical testing
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Permanent neonatal diabetes mellitus
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV004848570.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
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 … (more)
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. (less)
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Pathogenic
(Jun 27, 2024)
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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: SCV002013056.3
First in ClinVar: Nov 12, 2021 Last updated: Sep 16, 2024 |
Comment:
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 … (more)
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) (less)
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Pathogenic
(Sep 18, 2007)
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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: SCV000034565.3
First in ClinVar: Apr 04, 2013 Last updated: Dec 07, 2020 |
Comment on evidence:
In 4 affected members of a 3-generation family and an unrelated proband with permanent neonatal diabetes mellitus (PNDM4; 618858), Stoy et al. (2007) identified heterozygosity … (more)
In 4 affected members of a 3-generation family and an unrelated proband with permanent neonatal diabetes mellitus (PNDM4; 618858), Stoy et al. (2007) identified heterozygosity for a gly32-to-ser (G32S) substitution in the INS gene (residue B8 of the insulin molecule), predicted to induce a major conformational change that would disrupt folding. (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: SCV000091167.1
First in ClinVar: Oct 31, 2013 Last updated: Oct 31, 2013 |
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not provided
(Apr 03, 2015)
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no classification provided
Method: clinical testing
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Neonatal Diabetes Mellitus
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000052727.2
First in ClinVar: Apr 04, 2013 Last updated: Dec 29, 2015 |
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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: SCV000040549.2
First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2022 |
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Uncertain significance
(-)
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Flagged submission
flagged submission
Method: research
Reason: Outlier claim with insufficient supporting evidence
Source: ClinGen
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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: SCV004174201.1
First in ClinVar: Dec 09, 2023 Last updated: Dec 09, 2023 |
Comment:
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 … (more)
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. (less)
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Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more |
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 |
The KINGS Ins2 (+/G32S) Mouse: A Novel Model of β-Cell Endoplasmic Reticulum Stress and Human Diabetes. | Austin ALF | Diabetes | 2020 | PMID: 32994272 |
Biological behaviors of mutant proinsulin contribute to the phenotypic spectrum of diabetes associated with insulin gene mutations. | Wang H | Molecular and cellular endocrinology | 2020 | PMID: 32916194 |
Molecular and clinical characteristics of monogenic diabetes mellitus in southern Chinese children with onset before 3 years of age. | Lin Y | BMJ open diabetes research & care | 2020 | PMID: 32792356 |
Six years' experience with LipidSeq: clinical and research learnings from a hybrid, targeted sequencing panel for dyslipidemias. | Dron JS | BMC medical genomics | 2020 | PMID: 32041611 |
Identification of insulin gene variants in patients with neonatal diabetes in the Chinese population. | Fu J | Journal of diabetes investigation | 2020 | PMID: 31605659 |
Negative autoimmunity in a Spanish pediatric cohort suspected of type 1 diabetes, could it be monogenic diabetes? | Urrutia I | PloS one | 2019 | PMID: 31365591 |
Residual β cell function and monogenic variants in long-duration type 1 diabetes patients. | Yu MG | The Journal of clinical investigation | 2019 | PMID: 31264968 |
Genetic Confirmation Rate in Clinically Suspected Maturity-Onset Diabetes of the Young. | Brahm AJ | Canadian journal of diabetes | 2016 | PMID: 27634015 |
Bilateral cataracts in a 6-yr-old with new onset diabetes: a novel presentation of a known INS gene mutation. | Wasserman H | Pediatric diabetes | 2016 | PMID: 26530398 |
Diabetes associated with dominant insulin gene mutations: outcome of 24-month, sensor-augmented insulin pump treatment. | Ortolani F | Acta diabetologica | 2016 | PMID: 26239141 |
Permanent Neonatal Diabetes Mellitus. | Adam MP | - | 2016 | PMID: 20301620 |
Neonatal diabetes in Ukraine: incidence, genetics, clinical phenotype and treatment. | Globa E | Journal of pediatric endocrinology & metabolism : JPEM | 2015 | PMID: 26208381 |
Clinical and molecular characterization of neonatal diabetes and monogenic syndromic diabetes in Asian Indian children. | Jahnavi S | Clinical genetics | 2013 | PMID: 22831748 |
Clinical and molecular genetics of neonatal diabetes due to mutations in the insulin gene. | Støy J | Reviews in endocrine & metabolic disorders | 2010 | PMID: 20938745 |
Mutant proinsulin proteins associated with neonatal diabetes are retained in the endoplasmic reticulum and not efficiently secreted. | Park SY | Biochemical and biophysical research communications | 2010 | PMID: 20034470 |
In vitro processing and secretion of mutant insulin proteins that cause permanent neonatal diabetes. | Rajan S | American journal of physiology. Endocrinology and metabolism | 2010 | PMID: 19952343 |
Testing for monogenic diabetes among children and adolescents with antibody-negative clinically defined Type 1 diabetes. | Rubio-Cabezas O | Diabetic medicine : a journal of the British Diabetic Association | 2009 | PMID: 19900242 |
Insulin gene mutations as cause of diabetes in children negative for five type 1 diabetes autoantibodies. | Bonfanti R | Diabetes care | 2009 | PMID: 18840770 |
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 |
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Text-mined citations for rs80356664 ...
HelpRecord last updated Oct 08, 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.