ClinVar Genomic variation as it relates to human health
NM_000207.3(INS):c.188-31G>A
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.188-31G>A
Variation ID: 211186 Accession: VCV000211186.20
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11p15.5 11: 2160028 (GRCh38) [ NCBI UCSC ] 11: 2181258 (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 Oct 5, 2015 Feb 20, 2024 Oct 19, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000207.3:c.188-31G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
intron variant NM_001042376.3:c.187+757G>A intron variant NM_001185097.2:c.188-31G>A intron variant NM_001185098.2:c.188-31G>A intron variant NM_001291897.2:c.188-31G>A intron variant NC_000011.10:g.2160028C>T NC_000011.9:g.2181258C>T NG_007114.1:g.6167G>A NG_050578.1:g.6182G>A - Protein change
- Other names
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- Canonical SPDI
- NC_000011.10:2160027: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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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 | 199 | |
INS-IGF2 | - | - | - |
GRCh38 GRCh37 |
- | 319 |
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 (2) |
criteria provided, multiple submitters, no conflicts
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May 28, 2019 | RCV000193144.8 | |
Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Oct 19, 2023 | RCV000436891.14 | |
Likely risk allele (1) |
criteria provided, single submitter
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- | RCV002464141.1 | |
Likely risk allele (1) |
criteria provided, single submitter
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- | RCV003445689.1 |
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
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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
(Jun 30, 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: SCV000247610.1
First in ClinVar: Oct 05, 2015 Last updated: Oct 05, 2015 |
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Pathogenic
(Jun 28, 2016)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: not provided
Allele origin:
germline
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Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics
Accession: SCV000510900.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
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Pathogenic
(Jan 12, 2017)
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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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Eurofins Ntd Llc (ga)
Accession: SCV000705472.2
First in ClinVar: Oct 05, 2015 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 1
Sex: mixed
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Pathogenic
(May 28, 2019)
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criteria provided, single submitter
Method: clinical testing
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Permanent neonatal diabetes mellitus 1
Affected status: unknown
Allele origin:
unknown
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Mendelics
Accession: SCV001138202.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
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Likely risk allele
(-)
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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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Neonatal insulin-dependent diabetes mellitus
Affected status: unknown
Allele origin:
unknown
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Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic
Accession: SCV002605398.1
First in ClinVar: Dec 11, 2022 Last updated: Dec 11, 2022 |
Comment:
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 … (more)
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 rs797045623, yet. (less)
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Pathogenic
(Oct 25, 2021)
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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: SCV001818352.3
First in ClinVar: Sep 08, 2021 Last updated: Mar 04, 2023 |
Comment:
Published functional studies demonstrate a damaging effect; variant leads to the inclusion of 29 base pairs and an altered reading frame (Garin et al., 2012); … (more)
Published functional studies demonstrate a damaging effect; variant leads to the inclusion of 29 base pairs and an altered reading frame (Garin et al., 2012); In silico analysis, which includes splice predictors and evolutionary conservation, suggests this variant may impact gene splicing; This variant is associated with the following publications: (PMID: 25721872, 24622368, 25306193, 30414308, 22235272) (less)
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Pathogenic
(Aug 27, 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: SCV003439675.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024 |
Comment:
This variant has been observed in individual(s) with maturity onset diabetes of the young and/or permanent neonatal diabetes mellitus (PMID: 22235272, 24622368, 25721872, 30414308). In … (more)
This variant has been observed in individual(s) with maturity onset diabetes of the young and/or permanent neonatal diabetes mellitus (PMID: 22235272, 24622368, 25721872, 30414308). 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: 211186). Studies have shown that this variant results in activation of a cryptic splice site and introduces a new termination codon (PMID: 22235272). However the mRNA is not expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 2 of the INS gene. It does not directly change the encoded amino acid sequence of the INS protein. RNA analysis indicates that this variant induces altered splicing and likely disrupts the C-terminus of the protein. (less)
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Likely risk allele
(-)
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criteria provided, single submitter
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: SCV004174214.1
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 c.188-31G>A/rs797045623 with neonatal diabetes. (less)
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Pathogenic
(Oct 19, 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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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV004562713.1
First in ClinVar: Feb 20, 2024 Last updated: Feb 20, 2024 |
Comment:
The INS c.188-31G>A variant (rs797045623) is reported in the literature in multiple individuals and families affected with maturity onset diabetes of the young or permanent … (more)
The INS c.188-31G>A variant (rs797045623) is reported in the literature in multiple individuals and families affected with maturity onset diabetes of the young or permanent neonatal diabetes mellitus (Alkorta-Aranburu 2014, Busiah 2013, Dusatkova 2015, Garin 2012, Matsuno 2019). This variant is also reported in ClinVar (Variation ID: 211186), and is absent from the Genome Aggregation Database, but is considered a low confidence variant in the database. This is an intronic variant, and computational analyses (Alamut Visual Plus v.1.5.1) predict that this variant may impact splicing by creating a novel cryptic acceptor splice site and weakening the nearby canonical acceptor splice site. Additionally, functional studies demonstrate inclusion of 29 nucleotides of intron 2, and while this may not lead to nonsense-mediated decay, it is expected to create a truncated protein with an altered C-terminus (Garin 2012). Based on available information, this variant is considered to be pathogenic. References: Alkorta-Aranburu G et al. Phenotypic heterogeneity in monogenic diabetes: the clinical and diagnostic utility of a gene panel-based next-generation sequencing approach. Mol Genet Metab. 2014 Dec;113(4):315-320. PMID: 25306193. Busiah K et al. Neuropsychological dysfunction and developmental defects associated with genetic changes in infants with neonatal diabetes mellitus: a prospective cohort study (corrected). Lancet Diabetes Endocrinol. 2013 Nov;1(3):199-207. PMID: 24622368. Dusatkova L et al. Frameshift mutations in the insulin gene leading to prolonged molecule of insulin in two families with Maturity-Onset Diabetes of the Young. Eur J Med Genet. 2015 Apr;58(4):230-4. PMID: 25721872. Garin I et al. Permanent neonatal diabetes caused by creation of an ectopic splice site within the INS gene. PLoS One. 2012;7(1):e29205. PMID: 22235272. Matsuno S et al. Identification of a variant associated with early-onset diabetes in the intron of the insulin gene with exome sequencing. J Diabetes Investig. 2019 Jul;10(4):947-950. PMID: 30414308. (less)
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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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Identification of a variant associated with early-onset diabetes in the intron of the insulin gene with exome sequencing. | Matsuno S | Journal of diabetes investigation | 2019 | PMID: 30414308 |
Continued lessons from the INS gene: an intronic mutation causing diabetes through a novel mechanism. | Carmody D | Journal of medical genetics | 2015 | PMID: 26101329 |
Frameshift mutations in the insulin gene leading to prolonged molecule of insulin in two families with Maturity-Onset Diabetes of the Young. | Dusatkova L | European journal of medical genetics | 2015 | PMID: 25721872 |
INS-gene mutations: from genetics and beta cell biology to clinical disease. | Liu M | Molecular aspects of medicine | 2015 | PMID: 25542748 |
Neuropsychological dysfunction and developmental defects associated with genetic changes in infants with neonatal diabetes mellitus: a prospective cohort study [corrected]. | Busiah K | The lancet. Diabetes & endocrinology | 2013 | PMID: 24622368 |
Permanent neonatal diabetes caused by creation of an ectopic splice site within the INS gene. | Garin I | PloS one | 2012 | PMID: 22235272 |
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 |
The insulin gene in diabetes. | Pugliese A | Diabetes/metabolism research and reviews | 2002 | PMID: 11921414 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=INS | - | - | - | - |
Text-mined citations for rs797045623 ...
HelpRecord last updated Feb 28, 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.