VCV000431443.13 - ClinVar

NM_000207.3(INS):c.-152C>G

Germline

Classification

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.

(6)

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

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000207.3(INS):c.-152C>G

Variation ID: 431443 Accession: VCV000431443.13

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 11p15.5 11: 2161302 (GRCh38) [ NCBI UCSC ] 11: 2182532 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	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 1, 2013	Feb 14, 2024	Oct 31, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000207.3:c.-152C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NC_000011.10:g.2161302G>C
NC_000011.9:g.2182532G>C
NG_007114.1:g.4893C>G
NG_050578.1:g.4908C>G

... more HGVS ... less HGVS

Protein change

Other names

c.-331C>G

Canonical SPDI

NC_000011.10:2161301:G:C

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

Allele frequency Help The frequency of the allele represented by this VCV record.

Trans-Omics for Precision Medicine (TOPMed) 0.00001

Links

ClinGen: CA216276958 dbSNP: rs748749585 VarSome

Comment on variant

NCBI staff reviewed the sequence information reported in PubMed 20133622 to determine the location of this allele on current reference sequence.

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
Gene	OMIM	HI score Help 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.
INS		No evidence available	No evidence available	GRCh38 GRCh37	12	202

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.
Permanent neonatal diabetes mellitus	not provided (1)	no classification provided	-	RCV000055788.4
not specified	Pathogenic (1)	criteria provided, single submitter	Aug 20, 2019	RCV000501249.8
Diabetes mellitus, permanent neonatal 4 Hyperproinsulinemia Maturity-onset diabetes of the young type 10 Type 1 diabetes mellitus 2	Pathogenic (1)	criteria provided, single submitter	Dec 2, 2021	RCV002496902.1
Diabetes mellitus, permanent neonatal 4	no classifications from unflagged records (1)	no classifications from unflagged records	Jun 11, 2024	RCV003446090.2
not provided	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Oct 31, 2023	RCV003153665.3

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 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.
Pathogenic (Dec 02, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Type 1 diabetes mellitus 2 Maturity-onset diabetes of the young type 10 Hyperproinsulinemia Diabetes mellitus, permanent neonatal 4 Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002807824.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Pathogenic (Mar 14, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV003842452.1 First in ClinVar: Mar 26, 2023 Last updated: Mar 26, 2023	Comment: Variant often referred to as c.-331 C>G using alternate nomenclature; Published functional studies demonstrate a damaging effect on promoter activity (Garin et al., 2010; Bonnefond … (more) Variant often referred to as c.-331 C>G using alternate nomenclature; Published functional studies demonstrate a damaging effect on promoter activity (Garin et al., 2010; Bonnefond et al., 2011); A different variant at this position (c.-152 C>A) has been reported as likely pathogenic at GeneDx in association with neonatal diabetes; Nucleotide substitution has no predicted effect on splicing and is not conserved across species; This variant is associated with the following publications: (PMID: 29305569, 24622368, 32252216, 21592955, 20133622, 29183106, 31441606, 32656923, 34101350, 35140529, 33852861, 34458657) (less)
Pathogenic (Aug 20, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not specified Affected status: yes Allele origin: germline	Genetic Services Laboratory, University of Chicago Accession: SCV000595236.2 First in ClinVar: Aug 28, 2017 Last updated: Jun 12, 2020
Pathogenic (Oct 31, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV004294058.1 First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024	Publications: PubMed (2) PubMed: 20133622‚ 21592955 Comment: This variant occurs in a non-coding region of the INS gene. It does not change the encoded amino acid sequence of the INS protein. This … (more) This variant occurs in a non-coding region of the INS gene. It does not change the encoded amino acid sequence of the INS protein. This variant is present in population databases (rs748749585, gnomAD 0.1%). This variant has been observed in individuals with neonatal diabetes (PMID: 20133622). It has also been observed to segregate with disease in related individuals. This variant is also known as c.-331 C>G. ClinVar contains an entry for this variant (Variation ID: 431443). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects INS function (PMID: 21592955). For these reasons, this variant has been classified as Pathogenic. (less)
not provided (-)	no classification provided Method: literature only	Permanent neonatal diabetes mellitus Affected status: unknown Allele origin: germline	GeneReviews Accession: SCV000086754.3 First in ClinVar: Oct 01, 2013 Last updated: Oct 01, 2022	Publications: PubMed (3) PubMed: 20938745‚ 20133622‚ 21592955 BookShelf: NBK1447 BookShelf: NBK1447
Likely benign (-)	Flagged submission flagged submission (K & H Uppaluri Personalized Medicine Clinic Variant Classification & Assertion Criteria_Updated V.1) Method: research Reason: Outlier claim with insufficient supporting evidence Source: ClinGen	Diabetes mellitus, permanent neonatal 4 (Autosomal dominant inheritance) Affected status: unknown Allele origin: unknown	Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic Accession: SCV004174212.1 First in ClinVar: Dec 09, 2023 Last updated: Dec 09, 2023	Publications: PubMed (4) PubMed: 21592955‚ 34584998‚ 33852861‚ 32252216 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.rs748749585 variant is Prevalent in patients with Neonatal diabetes mellitus. However, the role of this particular variant is yet to be ascertained (less)
Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more

Comment:

Variant often referred to as c.-331 C>G using alternate nomenclature; Published functional studies demonstrate a damaging effect on promoter activity (Garin et al., 2010; Bonnefond et al., 2011); A different variant at this position (c.-152 C>A) has been reported as likely pathogenic at GeneDx in association with neonatal diabetes; Nucleotide substitution has no predicted effect on splicing and is not conserved across species; This variant is associated with the following publications: (PMID: 29305569, 24622368, 32252216, 21592955, 20133622, 29183106, 31441606, 32656923, 34101350, 35140529, 33852861, 34458657)

Comment:

This variant occurs in a non-coding region of the INS gene. It does not change the encoded amino acid sequence of the INS protein. This variant is present in population databases (rs748749585, gnomAD 0.1%). This variant has been observed in individuals with neonatal diabetes (PMID: 20133622). It has also been observed to segregate with disease in related individuals. This variant is also known as c.-331 C>G. ClinVar contains an entry for this variant (Variation ID: 431443). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects INS function (PMID: 21592955). For these reasons, this variant has been classified as Pathogenic.

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 gene can cause beta cell destruction.rs748749585 variant is Prevalent in patients with Neonatal diabetes mellitus. However, the role of this particular variant is yet to be ascertained

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.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Do second generation sequencing techniques identify documented genetic markers for neonatal diabetes mellitus?	Ali Khan I	Heliyon	2021	PMID: 34584998
Neonatal diabetes mutations disrupt a chromatin pioneering function that activates the human insulin gene.	Akerman I	Cell reports	2021	PMID: 33852861
A homozygous mutation in the insulin gene (INS) causing autosomal recessive neonatal diabetes in Saudi families.	Shaikh AA	Annals of pediatric endocrinology & metabolism	2020	PMID: 32252216
Permanent Neonatal Diabetes Mellitus.	Adam MP	-	2016	PMID: 20301620
Disruption of a novel Kruppel-like transcription factor p300-regulated pathway for insulin biosynthesis revealed by studies of the c.-331 INS mutation found in neonatal diabetes mellitus.	Bonnefond A	The Journal of biological chemistry	2011	PMID: 21592955
Clinical and molecular genetics of neonatal diabetes due to mutations in the insulin gene.	Støy J	Reviews in endocrine & metabolic disorders	2010	PMID: 20938745
Recessive mutations in the INS gene result in neonatal diabetes through reduced insulin biosynthesis.	Garin I	Proceedings of the National Academy of Sciences of the United States of America	2010	PMID: 20133622

Text-mined citations for rs748749585 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Oct 08, 2024

ClinVar Genomic variation as it relates to human health

NM_000207.3(INS):c.-152C>G

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs748749585 ...