VCV001705696.2 - ClinVar

NM_000219.6(KCNE1):c.106dup (p.Arg36fs)

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/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_000219.6(KCNE1):c.106dup (p.Arg36fs)

Variation ID: 1705696 Accession: VCV001705696.2

Type and length

Duplication, 1 bp

Location

Cytogenetic: 21q22.12 21: 34449528-34449529 (GRCh38) [ NCBI UCSC ] 21: 35821826-35821827 (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	Sep 17, 2022	Feb 28, 2024	Jun 30, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000219.6:c.106dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000210.2:p.Arg36fs	frameshift
NM_001127668.4:c.106dup	NP_001121140.1:p.Arg36fs	frameshift
NM_001127669.4:c.106dup	NP_001121141.1:p.Arg36fs	frameshift
NM_001127670.4:c.106dup	NP_001121142.1:p.Arg36fs	frameshift
NM_001270402.3:c.106dup	NP_001257331.1:p.Arg36fs	frameshift
NM_001270403.2:c.106dup	NP_001257332.1:p.Arg36fs	frameshift
NM_001270404.3:c.106dup	NP_001257333.1:p.Arg36fs	frameshift
NM_001270405.3:c.106dup	NP_001257334.1:p.Arg36fs	frameshift
NC_000021.9:g.34449534dup
NC_000021.8:g.35821832dup
NG_009091.1:g.66787dup
LRG_290:g.66787dup
LRG_290t1:c.101dup	LRG_290p1:p.Arg36Profs
LRG_290t2:c.101dup	LRG_290p2:p.Arg36Profs

... more HGVS ... less HGVS

Protein change

R36fs

Other names

Canonical SPDI

NC_000021.9:34449528:GGGGGG:GGGGGGG

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

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.
KCNE1		-	-	GRCh38 GRCh37	1261	1339

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 5	Likely pathogenic (1)	criteria provided, single submitter	Sep 1, 2022	RCV002284010.1
Long QT syndrome	Pathogenic (1)	criteria provided, single submitter	Jun 30, 2023	RCV003774938.2

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 (Sep 01, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Long QT syndrome 5 Affected status: yes Allele origin: germline	3billion Accession: SCV002573322.1 First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022	Comment: The variant is not observed in the gnomAD v2.1.1 dataset. Frameshift variant is predicted to result in a loss or disruption of normal protein function … (more) The variant is not observed in the gnomAD v2.1.1 dataset. Frameshift variant is predicted to result in a loss or disruption of normal protein function through protein truncation. The predicted truncated protein may be shortened by more than 10%. Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. (less) Clinical Features: Stroke disorder (present)
Pathogenic (Jun 30, 2023)	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: SCV004631326.1 First in ClinVar: Feb 28, 2024 Last updated: Feb 28, 2024	Publications: PubMed (6) PubMed: 10973849‚ 16922724‚ 17341399‚ 21070882‚ 30530868‚ 32058015 Comment: For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the KCNE1 protein in which other variant(s) (p.Arg98Trp) have … (more) For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the KCNE1 protein in which other variant(s) (p.Arg98Trp) have been determined to be pathogenic (PMID: 10973849, 16922724, 17341399, 21070882, 30530868, 32058015). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 1705696). This variant has not been reported in the literature in individuals affected with KCNE1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg36Profs*4) in the KCNE1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 94 amino acid(s) of the KCNE1 protein. (less)

Comment:

The variant is not observed in the gnomAD v2.1.1 dataset. Frameshift variant is predicted to result in a loss or disruption of normal protein function through protein truncation. The predicted truncated protein may be shortened by more than 10%. Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline.

Comment:

For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the KCNE1 protein in which other variant(s) (p.Arg98Trp) have been determined to be pathogenic (PMID: 10973849, 16922724, 17341399, 21070882, 30530868, 32058015). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 1705696). This variant has not been reported in the literature in individuals affected with KCNE1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg36Profs*4) in the KCNE1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 94 amino acid(s) of the KCNE1 protein.

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
Clinical and functional reappraisal of alleged type 5 long QT syndrome: Causative genetic variants in the KCNE1-encoded minK β-subunit.	Garmany R	Heart rhythm	2020	PMID: 32058015
Clinical and genetic profile of congenital long QT syndrome in Hong Kong: a 20-year experience in paediatrics.	Kwok SY	Hong Kong medical journal = Xianggang yi xue za zhi	2018	PMID: 30530868
Prospective, population-based long QT molecular autopsy study of postmortem negative sudden death in 1 to 40 year olds.	Skinner JR	Heart rhythm	2011	PMID: 21070882
N- and C-terminal KCNE1 mutations cause distinct phenotypes of long QT syndrome.	Ohno S	Heart rhythm	2007	PMID: 17341399
Spectrum of pathogenic mutations and associated polymorphisms in a cohort of 44 unrelated patients with long QT syndrome.	Millat G	Clinical genetics	2006	PMID: 16922724
Spectrum of mutations in long-QT syndrome genes. KVLQT1, HERG, SCN5A, KCNE1, and KCNE2.	Splawski I	Circulation	2000	PMID: 10973849

Text-mined citations for this variant ...

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_000219.6(KCNE1):c.106dup (p.Arg36fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...