VCV000211227.39 - ClinVar

NM_000525.4(KCNJ11):c.843C>T (p.Leu281=)

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.

(15)

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.

Conflicting classifications of pathogenicity
Uncertain significance(2); Benign(5); Likely benign(5)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000525.4(KCNJ11):c.843C>T (p.Leu281=)

Variation ID: 211227 Accession: VCV000211227.39

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 11p15.1 11: 17387249 (GRCh38) [ NCBI UCSC ] 11: 17408796 (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 5, 2015	Oct 20, 2024	Jan 31, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000525.4:c.843C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000516.3:p.Leu281=	synonymous
NM_001166290.2:c.582C>T	NP_001159762.1:p.Leu194=	synonymous
NM_001377296.1:c.582C>T	NP_001364225.1:p.Leu194=	synonymous
NM_001377297.1:c.582C>T	NP_001364226.1:p.Leu194=	synonymous
NC_000011.10:g.17387249G>A
NC_000011.9:g.17408796G>A
NG_012446.1:g.6411C>T

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000011.10:17387248:G:A

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.

0.00200 (A)

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

The Genome Aggregation Database (gnomAD) 0.00029

Trans-Omics for Precision Medicine (TOPMed) 0.00032

Exome Aggregation Consortium (ExAC) 0.00034

The Genome Aggregation Database (gnomAD), exomes 0.00040

1000 Genomes Project 30x 0.00187

1000 Genomes Project 0.00200

Links

ClinGen: CA208185 dbSNP: rs116392938 VarSome

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.
KCNJ11		-	-	GRCh38 GRCh37	466	492

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.
not specified	Benign/Likely benign (3)	criteria provided, multiple submitters, no conflicts	Sep 30, 2020	RCV000194182.14
not provided	Benign/Likely benign (6)	criteria provided, multiple submitters, no conflicts	Jan 31, 2024	RCV000960925.26
Hyperinsulinemic hypoglycemia, familial, 2	Uncertain significance (1)	criteria provided, single submitter	Apr 27, 2017	RCV001103552.5
Diabetes mellitus, transient neonatal, 3	Benign (1)	criteria provided, single submitter	Apr 27, 2017	RCV001105472.5
Permanent neonatal diabetes mellitus	Likely benign (1)	no assertion criteria provided	Oct 22, 2019	RCV001833136.2
Hyperinsulinemia	Uncertain significance (1)	criteria provided, single submitter	-	RCV002227089.2
Inborn genetic diseases	Likely benign (1)	criteria provided, single submitter	Sep 12, 2023	RCV003165435.2
Maturity-onset diabetes of the young type 13	Benign (1)	criteria provided, single submitter	Apr 27, 2017	RCV001105473.5

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.
Benign (Sep 30, 2020)	criteria provided, single submitter (Athena Diagnostics criteria) Method: clinical testing	not specified Affected status: unknown Allele origin: unknown	Athena Diagnostics Accession: SCV001880049.1 First in ClinVar: Sep 19, 2021 Last updated: Sep 19, 2021	Publications: PubMed (1) PubMed: 26740944
Likely benign (Nov 17, 2020)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001790225.1 First in ClinVar: Aug 18, 2021 Last updated: Aug 18, 2021	Comment: This variant is associated with the following publications: (PMID: 26740944)
Likely benign (May 23, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not specified Affected status: no Allele origin: germline	Genetic Services Laboratory, University of Chicago Accession: SCV000247654.2 First in ClinVar: Oct 05, 2015 Last updated: Jun 13, 2020
Uncertain significance (-)	criteria provided, single submitter (K&H Uppaluri Personalized Medicine Clinic Variant Classification & Assertion Criteria) Method: research	Hyperinsulinemia (Autosomal dominant inheritance) Affected status: unknown Allele origin: somatic	Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic Accession: SCV002505935.1 First in ClinVar: May 07, 2022 Last updated: May 07, 2022	Publications: PubMed (1) PubMed: 26740944 Comment: Mutations in KCNJ11 gene can generally cause decreased production and secretion of insulin. This can lead to MODY. However, the role of this particular variant … (more) Mutations in KCNJ11 gene can generally cause decreased production and secretion of insulin. This can lead to MODY. However, the role of this particular variant (rs116392938) of KCNJ11 gene in congenital hyperinsulinism and MODY remains uncertain. (less)
Benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	NOT SPECIFIED Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV000304670.1 First in ClinVar: Oct 02, 2016 Last updated: Oct 02, 2016
Likely benign (Feb 01, 2023)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV004136021.10 First in ClinVar: Nov 20, 2023 Last updated: Oct 20, 2024	Comment: KCNJ11: BP4, BP7 Number of individuals with the variant: 2
Likely benign (Sep 12, 2023)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Inborn genetic diseases Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV003904823.2 First in ClinVar: Apr 15, 2023 Last updated: May 01, 2024	Comment: This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of … (more) This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
Uncertain significance (Apr 27, 2017)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Hyperinsulinemic hypoglycemia, familial, 2 Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001260325.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Publications: PubMed (1) PubMed: 26740944 Comment: This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more) This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
Benign (Apr 27, 2017)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Diabetes mellitus, transient neonatal, 3 Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001262440.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Comment: This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more) This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. (less)
Benign (Apr 27, 2017)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Maturity-onset diabetes of the young type 13 Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001262441.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Comment: This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more) This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. (less)
Likely benign (Sep 14, 2022)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2021) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV003799950.2 First in ClinVar: Feb 13, 2023 Last updated: Mar 04, 2023
Benign (Jan 31, 2024)	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: SCV001107954.6 First in ClinVar: Dec 17, 2019 Last updated: Feb 20, 2024
Likely benign (Oct 22, 2019)	no assertion criteria provided Method: clinical testing	Permanent neonatal diabetes mellitus Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV002085115.1 First in ClinVar: Feb 13, 2022 Last updated: Feb 13, 2022
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV002034903.1 First in ClinVar: Dec 18, 2021 Last updated: Dec 18, 2021
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV002036849.1 First in ClinVar: Dec 18, 2021 Last updated: Dec 18, 2021
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Comment:

Mutations in KCNJ11 gene can generally cause decreased production and secretion of insulin. This can lead to MODY. However, the role of this particular variant (rs116392938) of KCNJ11 gene in congenital hyperinsulinism and MODY remains uncertain.

Comment:

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Comment:

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

Comment:

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.

Comment:

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.

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:

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.

Comment:

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Uncovering the molecular pathogenesis of congenital hyperinsulinism by panel gene sequencing in 32 Chinese patients.	Fan ZC	Molecular genetics & genomic medicine	2015	PMID: 26740944

Text-mined citations for rs116392938 ...

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 20, 2024

ClinVar Genomic variation as it relates to human health

NM_000525.4(KCNJ11):c.843C>T (p.Leu281=)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs116392938 ...