VCV000872042.31 - ClinVar

NM_153766.3(KCNJ1):c.939_942del (p.Glu315fs)

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.

(3)

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

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_153766.3(KCNJ1):c.939_942del (p.Glu315fs)

Variation ID: 872042 Accession: VCV000872042.31

Type and length

Deletion, 4 bp

Location

Cytogenetic: 11q24.3 11: 128839302-128839305 (GRCh38) [ NCBI UCSC ] 11: 128709197-128709200 (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	May 12, 2020	Oct 20, 2024	Jan 4, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_153766.3:c.939_942del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_722450.1:p.Glu315fs	frameshift
NM_000220.4:c.996_999del
NM_000220.6:c.996_999del	NP_000211.1:p.Glu334fs	frameshift
NM_153764.3:c.939_942del	NP_722448.1:p.Glu315fs	frameshift
NM_153765.3:c.990_993del	NP_722449.3:p.Glu332fs	frameshift
NM_153767.4:c.939_942del	NP_722451.1:p.Glu315fs	frameshift
NC_000011.10:g.128839302_128839305del
NC_000011.9:g.128709197_128709200del
NG_009379.1:g.33069_33072del

... more HGVS ... less HGVS

Protein change

E332fs, E334fs, E315fs

Other names

Canonical SPDI

NC_000011.10:128839301:CTTT:

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.

Exome Aggregation Consortium (ExAC) 0.00012

Trans-Omics for Precision Medicine (TOPMed) 0.00005

The Genome Aggregation Database (gnomAD), exomes 0.00010

The Genome Aggregation Database (gnomAD) 0.00003

Links

dbSNP: rs780691086 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.
KCNJ1		-	-	GRCh38 GRCh37	268	353

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	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Jan 4, 2024	RCV001092302.27

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 (Jul 25, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV004022846.1 First in ClinVar: Aug 05, 2023 Last updated: Aug 05, 2023	Comment: Frameshift variant predicted to result in protein truncation, as the last 58 amino acids are replaced with 34 different amino acids, and other loss-of-function variants … (more) Frameshift variant predicted to result in protein truncation, as the last 58 amino acids are replaced with 34 different amino acids, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (HGMD); Published functional studies demonstrate a damaging effect on protein localization and potassium channel function (Schwalbe et al., 1998); This variant is associated with the following publications: (PMID: 34345425, 32590952, 8841184, 9580661) (less)
Pathogenic (Jan 04, 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: SCV002228177.3 First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024	Publications: PubMed (4) PubMed: 8841184‚ 19096086‚ 9580661‚ 9002665 Comment: This sequence change creates a premature translational stop signal (p.Glu334Glyfs35) in the KCNJ1 gene. While this is not anticipated to result in nonsense mediated decay, … (more) This sequence change creates a premature translational stop signal (p.Glu334Glyfs35) in the KCNJ1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 58 amino acid(s) of the KCNJ1 protein. This variant is present in population databases (rs780691086, gnomAD 0.04%). This premature translational stop signal has been observed in individuals with Bartter syndrome (PMID: 8841184, 19096086). This variant is also known as T332 frameshift and T313fs. ClinVar contains an entry for this variant (Variation ID: 872042). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects KCNJ1 function (PMID: 9580661). This variant disrupts the C-terminus of the KCNJ1 protein. Other variant(s) that disrupt this region (p.Arg338*) have been observed in individuals with KCNJ1-related conditions (PMID: 9002665, 19096086). This suggests that this may be a clinically significant region of the protein. For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Oct 01, 2018)	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: SCV001248735.26 First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024	Number of individuals with the variant: 1

Comment:

Frameshift variant predicted to result in protein truncation, as the last 58 amino acids are replaced with 34 different amino acids, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (HGMD); Published functional studies demonstrate a damaging effect on protein localization and potassium channel function (Schwalbe et al., 1998); This variant is associated with the following publications: (PMID: 34345425, 32590952, 8841184, 9580661)

Comment:

This sequence change creates a premature translational stop signal (p.Glu334Glyfs*35) in the KCNJ1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 58 amino acid(s) of the KCNJ1 protein. This variant is present in population databases (rs780691086, gnomAD 0.04%). This premature translational stop signal has been observed in individuals with Bartter syndrome (PMID: 8841184, 19096086). This variant is also known as T332 frameshift and T313fs. ClinVar contains an entry for this variant (Variation ID: 872042). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects KCNJ1 function (PMID: 9580661). This variant disrupts the C-terminus of the KCNJ1 protein. Other variant(s) that disrupt this region (p.Arg338*) have been observed in individuals with KCNJ1-related conditions (PMID: 9002665, 19096086). This suggests that this may be a clinically significant region of the protein. For these reasons, this variant has been classified as Pathogenic.

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
Phenotype-genotype correlation in antenatal and neonatal variants of Bartter syndrome.	Brochard K	Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association	2009	PMID: 19096086
Functional consequences of ROMK mutants linked to antenatal Bartter's syndrome and implications for treatment.	Schwalbe RA	Human molecular genetics	1998	PMID: 9580661
Mutations in the gene encoding the inwardly-rectifying renal potassium channel, ROMK, cause the antenatal variant of Bartter syndrome: evidence for genetic heterogeneity. International Collaborative Study Group for Bartter-like Syndromes.	-	Human molecular genetics	1997	PMID: 9002665
Genetic heterogeneity of Bartter's syndrome revealed by mutations in the K+ channel, ROMK.	Simon DB	Nature genetics	1996	PMID: 8841184

Text-mined citations for rs780691086 ...

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_153766.3(KCNJ1):c.939_942del (p.Glu315fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs780691086 ...