VCV000842276.8 - ClinVar

NM_000218.3(KCNQ1):c.778C>T (p.Gln260Ter)

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.

(2)

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_000218.3(KCNQ1):c.778C>T (p.Gln260Ter)

Variation ID: 842276 Accession: VCV000842276.8

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 11p15.5 11: 2572107 (GRCh38) [ NCBI UCSC ] 11: 2593337 (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	Apr 15, 2020	Feb 20, 2024	Nov 3, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_000218.3:c.778C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000209.2:p.Gln260Ter	nonsense
NM_001406836.1:c.778C>T	NP_001393765.1:p.Gln260Ter	nonsense
NM_001406837.1:c.508C>T	NP_001393766.1:p.Gln170Ter	nonsense
NM_181798.2:c.397C>T	NP_861463.1:p.Gln133Ter	nonsense
NR_040711.2:n.671C>T
NC_000011.10:g.2572107C>T
NC_000011.9:g.2593337C>T
NG_008935.1:g.132117C>T
LRG_287:g.132117C>T
LRG_287t1:c.778C>T	LRG_287p1:p.Gln260Ter
LRG_287t2:c.397C>T	LRG_287p2:p.Gln133Ter

... more HGVS ... less HGVS

Protein change

Q260*, Q133*, Q170*

Other names

Canonical SPDI

NC_000011.10:2572106: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

dbSNP: rs1848346228 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.
KCNQ1		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh38 GRCh37	1721	2664

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.
Long QT syndrome	Pathogenic (1)	criteria provided, single submitter	Oct 14, 2021	RCV001044668.7
KCNQ1-related disorder	Pathogenic (1)	criteria provided, single submitter	Nov 3, 2022	RCV002298855.1

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 (Nov 03, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	KCNQ1-related disorder Affected status: yes Allele origin: germline	DASA Accession: SCV002588777.1 First in ClinVar: Nov 05, 2022 Last updated: Nov 05, 2022	Comment: The c.778C>T;p.(Gln260) variant creates a premature translational stop signal in the KCNQ1 gene. It is expected to result in an absent or disrupted protein product … (more) The c.778C>T;p.(Gln260) variant creates a premature translational stop signal in the KCNQ1 gene. It is expected to result in an absent or disrupted protein product - PVS1. ClinVar contains an entry for this variant (ClinVar ID: 842276) - PS4_supporting. This variant is not present in population databases (rs1848346228, 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
Pathogenic (Oct 14, 2021)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Long QT syndrome Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001208474.5 First in ClinVar: Apr 15, 2020 Last updated: Feb 20, 2024	Publications: PubMed (2) PubMed: 9323054‚ 19862833 Comment: For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 842276). This variant has not been … (more) For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 842276). This variant has not been reported in the literature in individuals affected with KCNQ1-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Gln260*) in the KCNQ1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in KCNQ1 are known to be pathogenic (PMID: 9323054, 19862833). (less)

Comment:

The c.778C>T;p.(Gln260*) variant creates a premature translational stop signal in the KCNQ1 gene. It is expected to result in an absent or disrupted protein product - PVS1. ClinVar contains an entry for this variant (ClinVar ID: 842276) - PS4_supporting. This variant is not present in population databases (rs1848346228, gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. In summary, the currently available evidence indicates that the variant is pathogenic.

Comment:

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 842276). This variant has not been reported in the literature in individuals affected with KCNQ1-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Gln260*) in the KCNQ1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in KCNQ1 are known to be pathogenic (PMID: 9323054, 19862833).

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
The genetic basis of long QT and short QT syndromes: a mutation update.	Hedley PL	Human mutation	2009	PMID: 19862833
Dominant-negative KvLQT1 mutations underlie the LQT1 form of long QT syndrome.	Shalaby FY	Circulation	1997	PMID: 9323054

Text-mined citations for rs1848346228 ...

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 Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_000218.3(KCNQ1):c.778C>T (p.Gln260Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1848346228 ...