ClinVar Genomic variation as it relates to human health
NM_000525.4(KCNJ11):c.175G>A (p.Val59Met)
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.
Pathogenic(5); Benign(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000525.4(KCNJ11):c.175G>A (p.Val59Met)
Variation ID: 8667 Accession: VCV000008667.23
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11p15.1 11: 17387917 (GRCh38) [ NCBI UCSC ] 11: 17409464 (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 Mar 10, 2024 Sep 24, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000525.4:c.175G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000516.3:p.Val59Met missense NM_001166290.2:c.-16-71G>A intron variant NM_001377296.1:c.-16-71G>A intron variant NM_001377297.1:c.-16-71G>A intron variant NC_000011.10:g.17387917C>T NC_000011.9:g.17409464C>T NG_012446.1:g.5743G>A - Protein change
- V59M
- Other names
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- Canonical SPDI
- NC_000011.10:17387916: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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KCNJ11 | - | - |
GRCh38 GRCh37 |
449 | - |
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
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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 (1) |
no assertion criteria provided
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Jul 1, 2006 | RCV000009201.15 | |
not provided (1) |
no classification provided
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- | RCV000030665.10 | |
Pathogenic (1) |
criteria provided, single submitter
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Feb 8, 2013 | RCV000146104.7 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Sep 24, 2023 | RCV000724752.10 | |
Pathogenic (1) |
criteria provided, single submitter
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- | RCV002051778.3 | |
Benign (1) |
criteria provided, single submitter
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- | RCV002227022.3 |
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. |
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Pathogenic
(Feb 08, 2013)
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criteria provided, single submitter
Method: clinical testing
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neonatal insulin-dependent diabetes mellitus
(Autosomal unknown)
Affected status: yes
Allele origin:
germline
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Genetic Services Laboratory, University of Chicago
Accession: SCV000193321.1
First in ClinVar: Nov 23, 2014 Last updated: Nov 23, 2014 |
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Pathogenic
(Sep 24, 2023)
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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: SCV004036933.1
First in ClinVar: Sep 30, 2023 Last updated: Sep 30, 2023 |
Comment:
Published functional studies demonstrate a damaging effect (Girard et al., 2009; Clark et al., 2010); Not observed in large population cohorts (gnomAD); This variant is … (more)
Published functional studies demonstrate a damaging effect (Girard et al., 2009; Clark et al., 2010); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22145471, 16123353, 23462667, 24855163, 16731837, 22252471, 19065048, 24582665, 23626843, 21682153, 20595581, 15115830, 17728498, 18307455, 17047922, 19774848, 19686306, 16670688, 26839896, 27681997, 29329106, 32792356, 32418263, 32820876, 32893419, 16087682, 36398453) (less)
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Pathogenic
(Jun 28, 2021)
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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: SCV002243636.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this variant affects KCNJ11 protein function (PMID: 19065048). Algorithms developed … (more)
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this variant affects KCNJ11 protein function (PMID: 19065048). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 8667). This variant has been observed in individual(s) with neonatal diabetes mellitus (PMID: 26839896, 27681997, 32792356). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (ExAC no frequency). This sequence change replaces valine with methionine at codon 59 of the KCNJ11 protein (p.Val59Met). The valine residue is highly conserved and there is a small physicochemical difference between valine and methionine. (less)
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Pathogenic
(Apr 30, 2015)
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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: SCV000224241.5
First in ClinVar: Jun 28, 2015 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 1
Sex: mixed
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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: SCV002318393.1
First in ClinVar: Apr 02, 2022 Last updated: Apr 02, 2022 |
Ethnicity/Population group: Indians
Geographic origin: India
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Benign
(-)
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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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Transitory neonatal diabetes mellitus
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
somatic
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Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic
Accession: SCV002505936.1
First in ClinVar: May 07, 2022 Last updated: May 07, 2022 |
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. However, … (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. However, this particular variant (rs80356616) is associated with DEND syndrome. (less)
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Pathogenic
(Jul 01, 2006)
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no assertion criteria provided
Method: literature only
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DIABETES MELLITUS, PERMANENT NEONATAL, 2, WITH NEUROLOGIC FEATURES
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000029418.6
First in ClinVar: Apr 04, 2013 Last updated: Mar 10, 2024 |
Comment on evidence:
In 2 unrelated males (ISPAD54 and ISPAD55) with permanent neonatal diabetes (PNDM2; 618856), Gloyn et al. (2004) found heterozygosity for a val59-to-met (V59M) mutation in … (more)
In 2 unrelated males (ISPAD54 and ISPAD55) with permanent neonatal diabetes (PNDM2; 618856), Gloyn et al. (2004) found heterozygosity for a val59-to-met (V59M) mutation in the KCNJ11 gene. One of the patients (ISPAD55) had muscle weakness and delayed motor and mental development. Proks et al. (2004) noted that 2 mutations in the same residue of Kir6.2, V59M and V59G (600937.0005), are associated with a more severe form of PNDM that may be accompanied by developmental delay, muscle weakness, and epilepsy, compared to PNDM caused by the mutations R201H (600937.0002) and R201C (600937.0004). They found that residue val59 lies some distance from the ATP-binding site, within the N-terminal region of the protein; moreover, val59 lies within the 'slide helix,' a domain postulated to be involved in the opening and closing (gating) of Kir channels. Functional expression studies in Xenopus oocytes indicated that the V59M and V59G mutations decreased ATP sensitivity indirectly by favoring the open conformation of the channel. Massa et al. (2005) found the V59M mutation in 4 unrelated Italian patients with PNDM. Two of the patients had motor and mental developmental delay. One of the patients was diagnosed at over 6 months of age (182 days). Massa et al. (2005) suggested that the designation 'permanent diabetes mellitus of infancy' (PDMI) replace 'permanent neonatal diabetes mellitus.' Gloyn et al. (2006) reported a patient (ANGERS1) with the V59M mutation who had PNDM and neurologic features, including mild motor developmental delay and axial hypotonia. (less)
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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: SCV000040729.2
First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2022 |
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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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Genetic Spectrum of Neonatal Diabetes. | Kocova M | Balkan journal of medical genetics : BJMG | 2021 | PMID: 33816067 |
Genotype-phenotype correlation of K(ATP) channel gene defects causing permanent neonatal diabetes in Indian patients. | Gopi S | Pediatric diabetes | 2021 | PMID: 32893419 |
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 |
Molecular and clinical features of K(ATP) -channel neonatal diabetes mellitus in Japan. | Hashimoto Y | Pediatric diabetes | 2017 | PMID: 27681997 |
Genetic Analysis and Follow-Up of 25 Neonatal Diabetes Mellitus Patients in China. | Cao B | Journal of diabetes research | 2016 | PMID: 26839896 |
Permanent Neonatal Diabetes Mellitus. | Adam MP | - | 2016 | PMID: 20301620 |
Expression of an activating mutation in the gene encoding the KATP channel subunit Kir6.2 in mouse pancreatic beta cells recapitulates neonatal diabetes. | Girard CA | The Journal of clinical investigation | 2009 | PMID: 19065048 |
KCNJ11 activating mutations are associated with developmental delay, epilepsy and neonatal diabetes syndrome and other neurological features. | Gloyn AL | European journal of human genetics : EJHG | 2006 | PMID: 16670688 |
Activating mutations in Kir6.2 and neonatal diabetes: new clinical syndromes, new scientific insights, and new therapy. | Hattersley AT | Diabetes | 2005 | PMID: 16123337 |
KCNJ11 activating mutations in Italian patients with permanent neonatal diabetes. | Massa O | Human mutation | 2005 | PMID: 15580558 |
Molecular basis of Kir6.2 mutations associated with neonatal diabetes or neonatal diabetes plus neurological features. | Proks P | Proceedings of the National Academy of Sciences of the United States of America | 2004 | PMID: 15583126 |
Kir6.2 mutations are a common cause of permanent neonatal diabetes in a large cohort of French patients. | Vaxillaire M | Diabetes | 2004 | PMID: 15448107 |
Activating mutations in the gene encoding the ATP-sensitive potassium-channel subunit Kir6.2 and permanent neonatal diabetes. | Gloyn AL | The New England journal of medicine | 2004 | PMID: 15115830 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=KCNJ11 | - | - | - | - |
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Text-mined citations for rs80356616 ...
HelpRecord last updated Mar 11, 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.