VCV000372887.13 - ClinVar

NM_001282534.2(KCNK9):c.392G>A (p.Arg131His)

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.

Likely 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_001282534.2(KCNK9):c.392G>A (p.Arg131His)

Variation ID: 372887 Accession: VCV000372887.13

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 8q24.3 8: 139618991 (GRCh38) [ NCBI UCSC ] 8: 140631234 (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	Jan 9, 2017	Mar 18, 2023	Aug 17, 2021

HGVS

Nucleotide	Protein	Molecular consequence
NM_001282534.2:c.392G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001269463.1:p.Arg131His	missense
NR_104210.2:n.523G>A		non-coding transcript variant
NC_000008.11:g.139618991C>T
NC_000008.10:g.140631234C>T
NG_012842.3:g.89066G>A
LRG_1042:g.89066G>A
LRG_1042t1:c.392G>A	LRG_1042p1:p.Arg131His

... more HGVS ... less HGVS

Protein change

R131H

Other names

Canonical SPDI

NC_000008.11:139618990:C:T

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.

Links

ClinGen: CA16042626 OMIM: 605874.0003 dbSNP: rs867543866 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.
KCNK9		No evidence available	No evidence available	GRCh38 GRCh37	62	125

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 provided	Likely pathogenic (2)	criteria provided, multiple submitters, no conflicts	Oct 22, 2020	RCV000413977.4
Birk-Barel syndrome	Likely pathogenic (4)	criteria provided, multiple submitters, no conflicts	Aug 17, 2021	RCV000679851.9
Inborn genetic diseases	Likely pathogenic (1)	criteria provided, single submitter	Dec 7, 2018	RCV001266147.2

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.
Likely pathogenic (Feb 09, 2016)	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000491421.1 First in ClinVar: Jan 09, 2017 Last updated: Jan 09, 2017	Comment: The R131H variant in the KCNK9 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The … (more) The R131H variant in the KCNK9 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The R131H variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R131H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. The R131H variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded. (less)
Likely pathogenic (Oct 22, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center Accession: SCV001468105.1 First in ClinVar: Jan 07, 2021 Last updated: Jan 07, 2021	Comment on evidence: PS2, PM2
Likely pathogenic (Aug 17, 2021)	criteria provided, single submitter (ICSLVariantClassificationCriteria RUGD 01 April 2020) Method: clinical testing	Birk-Barel syndrome Affected status: unknown Allele origin: unknown	Illumina Laboratory Services, Illumina Accession: SCV002034859.1 First in ClinVar: Dec 18, 2021 Last updated: Dec 18, 2021	Publications: PubMed (1) PubMed: 25326635 Comment: The KCNK9 c.392G>A (p.Arg131His) variant is a missense variant. A literature search was performed for the gene, cDNA change, and amino acid change. No publications … (more) The KCNK9 c.392G>A (p.Arg131His) variant is a missense variant. A literature search was performed for the gene, cDNA change, and amino acid change. No publications were found based on this search. However, multiple clinical laboratories in ClinVar have provided a likely pathogenic classification for this variant, which was noted to have occurred de novo in a male patient who was tested by the Baylor Genetics laboratory, and whose information was presumably published (Yang et al. 2014). This variant is not found in version 2.1.1 or version 3.1.1 of the Genome Aggregation Database despite its location in a region of good sequence coverage, which suggests the variant is rare. Multiple lines of computational evidence suggest that this variant will have a deleterious impact on the protein. This variant was identified in a de novo state. Based on the available evidence, the p.Arg131His variant is classified as likely pathogenic for KCNK9-imprinting syndrome, also known as Birk-Barel syndrome. (less)
Likely pathogenic (Jul 01, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Birk-Barel syndrome Affected status: yes Allele origin: de novo	Department of Genetics, Rouen University Hospital, Normandy Center for Genomic and Personalized Medicine Accession: SCV002102961.1 First in ClinVar: Mar 12, 2022 Last updated: Mar 12, 2022	Sex: male
Likely pathogenic (Dec 07, 2018)	criteria provided, single submitter (Ambry exome assertion method (8-5-2015)) Method: clinical testing	Inborn genetic diseases Affected status: yes Allele origin: germline	Ambry Genetics Accession: SCV001444319.2 First in ClinVar: Nov 21, 2020 Last updated: Jan 07, 2023	Publications: PubMed (2) PubMed: 29165669‚ 25326635 Number of individuals with the variant: 1 Clinical Features: Frequent falls (present) , Muscular hypotonia (present) , Global developmental delay (present) , Intellectual disability (present) , Supernumerary nipple (present) , Cleft palate (present) , … (more) Frequent falls (present) , Muscular hypotonia (present) , Global developmental delay (present) , Intellectual disability (present) , Supernumerary nipple (present) , Cleft palate (present) , Congenital velopharyngeal incompetence (present) , Attention deficit hyperactivity disorder (present) , Tremor (present) , Narrow forehead (present) , Microcephaly (present) , Poor coordination (present) , Abnormality of the tongue (present) , Nasal speech (present) , Retrognathia (present) (less) Sex: female Ethnicity/Population group: Unknown
Likely pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Birk-Barel syndrome Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV000807197.3 First in ClinVar: Sep 17, 2018 Last updated: Mar 18, 2023	Publications: PubMed (1) PubMed: 25326635
Pathogenic (Jan 25, 2023)	no assertion criteria provided Method: literature only	BIRK-BAREL SYNDROME Affected status: not provided Allele origin: germline	OMIM Accession: SCV003841024.1 First in ClinVar: Mar 18, 2023 Last updated: Mar 18, 2023	Publications: PubMed (1) PubMed: 35698242 Comment on evidence: In patients from 5 unrelated families (families 3-7) with Birk-Barel syndrome (BIBARS; 612292), Cousin et al. (2022) identified a de novo heterozygous c.392G-A transition (c.392G-A, … (more) In patients from 5 unrelated families (families 3-7) with Birk-Barel syndrome (BIBARS; 612292), Cousin et al. (2022) identified a de novo heterozygous c.392G-A transition (c.392G-A, NM_001282534.1) in the KCNK9 gene, resulting in an arg131-to-his (R131H) substitution. The mutation, which was found by whole-exome sequencing, was not present in the gnomAD database. Whole-cell patch-clamp studies demonstrated that the mutation resulted in significantly increased outward currents compared to wildtype KCNK9. (less)

Comment:

The R131H variant in the KCNK9 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The R131H variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R131H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. The R131H variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded.

Comment:

The KCNK9 c.392G>A (p.Arg131His) variant is a missense variant. A literature search was performed for the gene, cDNA change, and amino acid change. No publications were found based on this search. However, multiple clinical laboratories in ClinVar have provided a likely pathogenic classification for this variant, which was noted to have occurred de novo in a male patient who was tested by the Baylor Genetics laboratory, and whose information was presumably published (Yang et al. 2014). This variant is not found in version 2.1.1 or version 3.1.1 of the Genome Aggregation Database despite its location in a region of good sequence coverage, which suggests the variant is rare. Multiple lines of computational evidence suggest that this variant will have a deleterious impact on the protein. This variant was identified in a de novo state. Based on the available evidence, the p.Arg131His variant is classified as likely pathogenic for KCNK9-imprinting syndrome, also known as Birk-Barel syndrome.

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
Gain and loss of TASK3 channel function and its regulation by novel variation cause KCNK9 imprinting syndrome.	Cousin MA	Genome medicine	2022	PMID: 35698242
ClinVar: improving access to variant interpretations and supporting evidence.	Landrum MJ	Nucleic acids research	2018	PMID: 29165669
Molecular findings among patients referred for clinical whole-exome sequencing.	Yang Y	JAMA	2014	PMID: 25326635

Text-mined citations for rs867543866 ...

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 Aug 06, 2023

ClinVar Genomic variation as it relates to human health

NM_001282534.2(KCNK9):c.392G>A (p.Arg131His)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs867543866 ...