VCV000211230.18 - ClinVar

NM_000525.4(KCNJ11):c.881C>T (p.Thr294Met)

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.

(7)

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
Pathogenic(2); Likely pathogenic(2); Uncertain risk allele(1)

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.881C>T (p.Thr294Met)

Variation ID: 211230 Accession: VCV000211230.18

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 11p15.1 11: 17387211 (GRCh38) [ NCBI UCSC ] 11: 17408758 (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	Feb 14, 2024	Jan 11, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000525.4:c.881C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000516.3:p.Thr294Met	missense
NM_001166290.2:c.620C>T	NP_001159762.1:p.Thr207Met	missense
NM_001377296.1:c.620C>T	NP_001364225.1:p.Thr207Met	missense
NM_001377297.1:c.620C>T	NP_001364226.1:p.Thr207Met	missense
NC_000011.10:g.17387211G>A
NC_000011.9:g.17408758G>A
NG_012446.1:g.6449C>T

... more HGVS ... less HGVS

Protein change

T294M, T207M

Other names

Canonical SPDI

NC_000011.10:17387210: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.

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

Trans-Omics for Precision Medicine (TOPMed) 0.00002

The Genome Aggregation Database (gnomAD) 0.00001

Exome Aggregation Consortium (ExAC) 0.00002

The Genome Aggregation Database (gnomAD), exomes 0.00002

Links

ClinGen: CA276941 dbSNP: rs780957825 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.
Hyperinsulinemic hypoglycemia, familial, 2	Pathogenic (1)	criteria provided, single submitter	May 18, 2015	RCV000192330.9
Diabetes mellitus, transient neonatal, 3	Likely pathogenic (1)	no assertion criteria provided	Aug 18, 2017	RCV000984004.4
not provided	Pathogenic (1)	criteria provided, single submitter	Jan 11, 2024	RCV001385879.10
Diabetes mellitus, permanent neonatal 2 Diabetes mellitus, transient neonatal, 3 Hyperinsulinemic hypoglycemia, familial, 2 Maturity-onset diabetes of the young type 13 Type 2 diabetes mellitus	Likely pathogenic (1)	criteria provided, single submitter	Jun 30, 2021	RCV001535984.6
Hyperinsulinemia	Uncertain risk allele (1)	criteria provided, single submitter	-	RCV002227091.4
Maturity onset diabetes mellitus in young	no classifications from unflagged records (1)	no classifications from unflagged records	Jun 12, 2024	RCV002227090.5
Type 2 diabetes mellitus	Likely pathogenic (1)	criteria provided, single submitter	May 23, 2023	RCV003462300.1

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 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 (May 18, 2015)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hyperinsulinemic hypoglycemia, familial, 2 Affected status: yes Allele origin: germline	Genetic Services Laboratory, University of Chicago Accession: SCV000247658.1 First in ClinVar: Oct 05, 2015 Last updated: Oct 05, 2015
Likely pathogenic (Jun 30, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Type 2 diabetes mellitus Hyperinsulinemic hypoglycemia, familial, 2 Diabetes mellitus, transient neonatal, 3 Maturity-onset diabetes of the young type 13 Diabetes mellitus, permanent neonatal 2 Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV001752654.1 First in ClinVar: Jul 18, 2021 Last updated: Jul 18, 2021 Comment: This variant has been detected in individual(s) who were sent for testing of Renasight - kidney gene panel.
Uncertain risk allele (-)	criteria provided, single submitter (K & H Uppaluri Personalized Medicine Clinic Variant Classification & Assertion Criteria_Updated V.1) Method: research	Hyperinsulinemia (Autosomal dominant inheritance) Affected status: yes Allele origin: somatic	Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic Accession: SCV002506483.1 First in ClinVar: May 07, 2022 Last updated: May 07, 2022	Publications: PubMed (1) PubMed: 20589481 Comment: Mutations in KCNJ11 gene can cause decreased production and secretion of insulin. This can lead to MODY which may be responsive to oral sulfonylureas. This … (more) Mutations in KCNJ11 gene can cause decreased production and secretion of insulin. This can lead to MODY which may be responsive to oral sulfonylureas. This particular variant (rs780957825) is associated with Familial hyperinsulinemic hypoglycemia and response to diazoxide therapy. (less)
Likely pathogenic (May 23, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Type 2 diabetes mellitus Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004198064.1 First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023
Pathogenic (Jan 11, 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: SCV001585887.4 First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024	Publications: PubMed (4) PubMed: 20049716‚ 20589481‚ 20685672‚ 24434300 Comment: This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 294 of the KCNJ11 protein (p.Thr294Met). … (more) This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 294 of the KCNJ11 protein (p.Thr294Met). This variant is present in population databases (rs780957825, gnomAD 0.01%). This missense change has been observed in individuals with autosomal recessive diffuse or paternally inherited focal hyperinsulinism (PMID: 20049716, 20589481, 20685672, 24434300). ClinVar contains an entry for this variant (Variation ID: 211230). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt KCNJ11 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects KCNJ11 function (PMID: 20049716). For these reasons, this variant has been classified as Pathogenic. (less)
Likely pathogenic (Aug 18, 2017)	no assertion criteria provided Method: clinical testing	Diabetes mellitus, transient neonatal, 3 Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000793561.2 First in ClinVar: Aug 05, 2018 Last updated: Dec 23, 2019	Publications: PubMed (5) PubMed: 24434300‚ 20049716‚ 20685672‚ 25639667‚ 20589481
Uncertain significance (-)	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	Maturity onset diabetes mellitus in young (Autosomal dominant inheritance) Affected status: unknown Allele origin: somatic	Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic Accession: SCV002506481.1 First in ClinVar: May 07, 2022 Last updated: May 07, 2022	Publications: PubMed (1) PubMed: 20589481 Comment: Mutations in KCNJ11 gene can cause decreased production and secretion of insulin. This can lead to MODY which may be responsive to oral sulfonylureas. This … (more) Mutations in KCNJ11 gene can cause decreased production and secretion of insulin. This can lead to MODY which may be responsive to oral sulfonylureas. This particular variant (rs780957825) is associated with Familial hyperinsulinemic hypoglycemia and response to diazoxide therapy. However, no sufficient evidence is found to ascertain the significance of rs780957825 in MODY yet. (less)
Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more

Comment:

Mutations in KCNJ11 gene can cause decreased production and secretion of insulin. This can lead to MODY which may be responsive to oral sulfonylureas. This particular variant (rs780957825) is associated with Familial hyperinsulinemic hypoglycemia and response to diazoxide therapy.

Comment:

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 294 of the KCNJ11 protein (p.Thr294Met). This variant is present in population databases (rs780957825, gnomAD 0.01%). This missense change has been observed in individuals with autosomal recessive diffuse or paternally inherited focal hyperinsulinism (PMID: 20049716, 20589481, 20685672, 24434300). ClinVar contains an entry for this variant (Variation ID: 211230). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt KCNJ11 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects KCNJ11 function (PMID: 20049716). For these reasons, this variant has been classified as Pathogenic.

Comment:

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
Congenital hyperinsulinism in Chinese patients: 5-yr treatment outcome of 95 clinical cases with genetic analysis of 55 cases.	Gong C	Pediatric diabetes	2016	PMID: 25639667
Long-term follow-up and mutation analysis of 27 chinese cases of congenital hyperinsulinism.	Su C	Hormone research in paediatrics	2014	PMID: 24434300
ABCC8 and KCNJ11 molecular spectrum of 109 patients with diazoxide-unresponsive congenital hyperinsulinism.	Bellanné-Chantelot C	Journal of medical genetics	2010	PMID: 20685672
Persistent hyperinsulinemic hypoglycemia of infancy due to homozygous KCNJ11 (T294M) mutation.	Ilamaran V	Indian journal of pediatrics	2010	PMID: 20589481
Adjacent mutations in the gating loop of Kir6.2 produce neonatal diabetes and hyperinsulinism.	Shimomura K	EMBO molecular medicine	2009	PMID: 20049716

Text-mined citations for rs780957825 ...

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_000525.4(KCNJ11):c.881C>T (p.Thr294Met)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs780957825 ...