ClinVar Genomic variation as it relates to human health
NM_001282534.2(KCNK9):c.706G>A (p.Gly236Arg)
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_001282534.2(KCNK9):c.706G>A (p.Gly236Arg)
Variation ID: 4741 Accession: VCV000004741.16
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 8q24.3 8: 139618677 (GRCh38) [ NCBI UCSC ] 8: 140630920 (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 11, 2015 Apr 6, 2024 Mar 17, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001282534.2:c.706G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001269463.1:p.Gly236Arg missense NR_104210.2:n.837G>A non-coding transcript variant NC_000008.11:g.139618677C>T NC_000008.10:g.140630920C>T NG_012842.3:g.89380G>A LRG_1042:g.89380G>A LRG_1042t1:c.706G>A LRG_1042p1:p.Gly236Arg Q9NPC2:p.Gly236Arg - Protein change
- G236R
- Other names
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- Canonical SPDI
- NC_000008.11:139618676: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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KCNK9 | No evidence available | No evidence available |
GRCh38 GRCh37 |
50 | 113 |
Conditions - Germline
Condition
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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 (6) |
criteria provided, multiple submitters, no conflicts
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Mar 17, 2024 | RCV000005007.21 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Nov 1, 2021 | RCV000203121.14 |
Submissions - Germline
Classification
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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
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
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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
(Apr 12, 2015)
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criteria provided, single submitter
Method: clinical testing
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Not provided
Affected status: unknown
Allele origin:
unknown
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Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia
Accession: SCV000258111.2
First in ClinVar: Dec 27, 2015 Last updated: Dec 27, 2015 |
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Pathogenic
(Oct 23, 2020)
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criteria provided, single submitter
Method: clinical testing
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not provided
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001447625.1
First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020 |
Clinical Features:
Dolichocephaly (present) , Cognitive impairment (present) , Hypotonia (present) , Kyphoscoliosis (present) , Developmental dysplasia of the hip (present)
Sex: male
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Pathogenic
(Feb 07, 2020)
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criteria provided, single submitter
Method: clinical testing
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Birk-Barel syndrome
Affected status: unknown
Allele origin:
unknown
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Illumina Laboratory Services, Illumina
Accession: SCV001251615.2
First in ClinVar: May 31, 2020 Last updated: Mar 04, 2023 |
Comment:
The KCNK9 c.706G>A (p.Gly236Arg) variant is a missense variant that has been reported in a heterozygous state in two studies (Barel et al. 2008; Graham … (more)
The KCNK9 c.706G>A (p.Gly236Arg) variant is a missense variant that has been reported in a heterozygous state in two studies (Barel et al. 2008; Graham et al. 2016). The variant was reported in a de novo state in two unrelated individuals with KCKN9 imprinting syndrome in Graham et al. (2016), and in at least 11 affected individuals showing segregation analysis in a large Israeli Arab family consistent with autosomal dominant inheritance with paternal imprinting (Barel et al. 2008). Additionally, de novo inheritance was noted in two unrelated affected individuals that carried a different nucleotide change resulting in the same amino acid consequence, c.706G>C (p.Gly236Arg). The p.Gly236Arg variant is not reported in the Genome Aggregation Database in a region of good sequence coverage, suggesting that it is a rare variant. Functional studies in mice expressing the mutant showed significantly higher calcium transients as compared to controls (Bando et al. 2014). Based on the collective evidence and application of the ACMG criteria, the p.Gly236Arg variant is classified as pathogenic for KCKN9 imprinting syndrome. (less)
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Pathogenic
(May 07, 2021)
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criteria provided, single submitter
Method: clinical testing
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Birk-Barel syndrome
Affected status: yes
Allele origin:
de novo
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Accession: SCV003921823.1
First in ClinVar: May 06, 2023 Last updated: May 06, 2023 |
Comment:
0104 - Dominant negative is a known mechanism of disease in this gene and is associated with Birk-Barel syndrome (MIM#612292). (I) 0107 - This gene … (more)
0104 - Dominant negative is a known mechanism of disease in this gene and is associated with Birk-Barel syndrome (MIM#612292). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0113 - This gene is known to be imprinted. KCNK9 is expressed from the maternal allele (imprinted with paternal silencing) (PMID: 27151206). In this individual, this variant is located on the maternal allele. (I) 0115 - Variants in this gene are known to have variable expressivity. Intra-familial variability in terms of intellectual disability has been described in a large kindred (PMID: 18678320). (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to arginine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region in DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been found de novo in at least four patients and proven to segregate in a large Isreali Arab kindred (PMID: 18678320, 27151206). Diagnostic laboratories in Clinvar have classified this variant to be pathogenic (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed, by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
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Pathogenic
(Jun 10, 2022)
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criteria provided, single submitter
Method: clinical testing
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Birk-Barel syndrome
Affected status: yes
Allele origin:
germline
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DASA
Accession: SCV002526399.1
First in ClinVar: Jun 18, 2022 Last updated: Jun 18, 2022 |
Comment:
The c.706G>A;p.(Gly236Arg) missense change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 465213; PMID: 18678320; 23236211; 27151206; … (more)
The c.706G>A;p.(Gly236Arg) missense change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 465213; PMID: 18678320; 23236211; 27151206; 28882594; 30690205) - PS4.Same amino acid change as a previously established Pathogenic variant regardless of nucleotide change (c.706G>C; p.(Gly236Arg); PMID: 28333430; ClinVar ID:397636; GeneReviews: NBK425128) - PS1. This variant is not present in population databases:rs121908332, gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. In summary, the currently available evidence indicates that the variant is Pathogenic (less)
Number of individuals with the variant: 1
Sex: male
Geographic origin: Brazil
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Pathogenic
(Nov 01, 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: SCV000617204.4
First in ClinVar: Dec 19, 2017 Last updated: Mar 04, 2023 |
Comment:
Published functional studies indicate that G236R results in a reduction of current suggestive of a dominant-negative effect (Barel et al., 2008; Veale et al., 2014); … (more)
Published functional studies indicate that G236R results in a reduction of current suggestive of a dominant-negative effect (Barel et al., 2008; Veale et al., 2014); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 18678320, 24342771, 27378938, 27151206, 30577886, 23236211) (less)
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Pathogenic
(Mar 17, 2024)
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criteria provided, single submitter
Method: research
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Birk-Barel syndrome
Affected status: unknown
Allele origin:
germline
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Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004805028.2
First in ClinVar: Mar 30, 2024 Last updated: Apr 06, 2024 |
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Pathogenic
(Dec 12, 2016)
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no assertion criteria provided
Method: literature only
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Birk-Barel syndrome
Affected status: unknown
Allele origin:
germline
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GeneReviews
Accession: SCV000537866.1
First in ClinVar: Oct 11, 2015 Last updated: Oct 11, 2015 |
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Pathogenic
(Aug 01, 2008)
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no assertion criteria provided
Method: literature only
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BIRK-BAREL SYNDROME
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000025183.4
First in ClinVar: Apr 04, 2013 Last updated: Mar 18, 2023 |
Comment on evidence:
In a large Israeli-Arab kindred presenting with an apparently maternally transmitted syndrome of mental retardation and dysmorphic features (BIBARS; 612292), Barel et al. (2008) identified … (more)
In a large Israeli-Arab kindred presenting with an apparently maternally transmitted syndrome of mental retardation and dysmorphic features (BIBARS; 612292), Barel et al. (2008) identified a G-to-A transition at nucleotide 770 (c.770G-A, NM_016601) in exon 2 of the KCNK9 gene, resulting in a glycine-to-arginine substitution at codon 236 (G236R). Analysis of all 27 DNA samples of the kindred was compatible with the mutation being associated with the disease phenotype, implying dominant inheritance with paternal imprinting. The G236R mutation is expected to lie within the ion-conduction pathway of the channel, and expression of mutant cRNAs in Xenopus laevis oocytes resulted in no measurable current. Coexpression of mutant and wildtype channels resulted in an approximately 4-fold decrease in wildtype currents, indicating a dominant-negative effect. A dominant-negative effect was also observed when the KCNK9 mutant was coexpressed with KCNK3 (603220). By exome sequencing in 4 unrelated children with developmental delay and central hypotonia, Graham et al. (2016) identified de novo heterozygosity for the G236R mutation in the KCNK9 gene. In a patient (family 23) with BIBARS, Cousin et al. (2022) identified a de novo heterozygous c.706G-A transition (NM_001282534.1) in the KCNK9 gene, resulting in the G236R substitution. The mutation, which was identified by whole-exome sequencing, was not present in the gnomAD database (v2.1.1). Whole-cell patch-clamp studies demonstrated that the mutation resulted in significantly reduced outward currents compared to wildtype KCNK9. (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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Gain and loss of TASK3 channel function and its regulation by novel variation cause KCNK9 imprinting syndrome. | Cousin MA | Genome medicine | 2022 | PMID: 35698242 |
Novel variant in the KCNK9 gene in a girl with Birk Barel syndrome. | Šedivá M | European journal of medical genetics | 2020 | PMID: 30690205 |
Terbinafine is a novel and selective activator of the two-pore domain potassium channel TASK3. | Wright PD | Biochemical and biophysical research communications | 2017 | PMID: 28882594 |
KCNK9 Imprinting Syndrome. | Adam MP | - | 2017 | PMID: 28333430 |
KCNK9 imprinting syndrome-further delineation of a possible treatable disorder. | Graham JM Jr | American journal of medical genetics. Part A | 2016 | PMID: 27151206 |
Dysfunction of KCNK potassium channels impairs neuronal migration in the developing mouse cerebral cortex. | Bando Y | Cerebral cortex (New York, N.Y. : 1991) | 2014 | PMID: 23236211 |
Maternally inherited Birk Barel mental retardation dysmorphism syndrome caused by a mutation in the genomically imprinted potassium channel KCNK9. | Barel O | American journal of human genetics | 2008 | PMID: 18678320 |
Text-mined citations for rs121908332 ...
HelpRecord last updated May 12, 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.