VCV003235891.1 - ClinVar

NM_000218.3(KCNQ1):c.1812_*143del (p.Gln604_Ter677delinsXaa)

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.

(1)

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, single submitter

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000218.3(KCNQ1):c.1812_*143del (p.Gln604_Ter677delinsXaa)

Variation ID: 3235891 Accession: VCV003235891.1

Type and length

Deletion, 363 bp

Location

Cytogenetic: 11p15.4 11: 2847777-2848139 (GRCh38) [ NCBI UCSC ] 11: 2869007-2869369 (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 19, 2024	May 19, 2024	Aug 23, 2021

HGVS

Nucleotide	Protein	Molecular consequence
NM_000218.3:c.1812_*143del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000209.2:p.Gln604_Ter677delinsXaa	stop lost
NM_001406836.1:c.1716_*143del	NP_001393765.1:p.Gln572_Ter645delinsXaa	stop lost
NM_001406837.1:c.1542_*143del	NP_001393766.1:p.Gln514_Ter587delinsXaa	stop lost
NM_001406838.1:c.1272_*143del	NP_001393767.1:p.Gln424_Ter497delinsXaa	stop lost
NM_001406839.1:c.324_*143del	NP_001393768.1:p.Gln108_Ter181delinsXaa	stop lost
NM_181798.2:c.1431_*143del	NP_861463.1:p.Gln477_Ter550delinsXaa	stop lost
NR_040711.2:n.1705_2067del363
NC_000011.10:g.2847784_2848146del
NC_000011.9:g.2869014_2869376del
NG_008935.1:g.407794_408156del
LRG_287:g.407794_408156del
LRG_287t1:c.1812_*143del363	LRG_287p1:p.Gln604_Ter(677_?)(?)
LRG_287t2:c.1431_*143del363	LRG_287p2:p.Gln477_Ter(550_?)(?)

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

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.
KCNQ1		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh38 GRCh37	1721	2664
KCNQ1-AS1	-	-	-	GRCh38 GRCh38	-	245

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.
Atrial fibrillation, familial, 3 Long QT syndrome 1 Short QT syndrome type 2	Likely pathogenic (1)	criteria provided, single submitter	Aug 23, 2021	RCV004555152.2

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 (Aug 23, 2021)	criteria provided, single submitter (NYGC Assertion Criteria 2020) Method: clinical testing	Long QT syndrome 1 Short QT syndrome type 2 Atrial fibrillation, familial, 3 Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases. Affected status: unknown Allele origin: inherited	New York Genome Center Study: PrenatalSEQ Accession: SCV005044065.1 First in ClinVar: May 19, 2024 Last updated: May 19, 2024	Comment: This inherited heterozygous 363 base-pair genomic deletion is in the last exon (exon 16) of the KCNQ1 gene. The deleted region contains >90% of protein-coding … (more) This inherited heterozygous 363 base-pair genomic deletion is in the last exon (exon 16) of the KCNQ1 gene. The deleted region contains >90% of protein-coding part of the last exon as well as part of 3’ Untranslated Region (3’UTR) of the KCNQ1 gene. The resultant predicted protein product would lack the last seventy-three amino acid residues (>10% of the protein) and would include 27 out-of-frame residues (c.1812_143del, p.(Gln604_Ser676delins(27))). Although this genomic deletion has not been reported previously in the literature or in the population databases, other frameshift variants in the last exon of KCNQ1 have been reported in the literature and ClinVar as likely pathogenic and pathogenic [ClinVar ID:53027, 928774] [PMID: 10024302, 16981927, 19716085, 19825999, 23098067, 23631430, 25187895]. Furthermore, functional studies performed on a frameshift variant located in the last exon (p.Pro631fs) showed that replacing these amino acid residues with out-of-frame residues might impair cell surface expression of the protein due to retention in the endoplasmic reticulum [PMID:19825999]. Based on the available evidence, this inherited c.1812_143del variant is reported as Likely pathogenic. (less) Clinical Features: Double outlet right ventricle (present) , Coarctation in the transverse aortic arch (present) , Ventricular septal defect (present) Age: 20-29 weeks gestation Secondary finding: yes

Comment:

This inherited heterozygous 363 base-pair genomic deletion is in the last exon (exon 16) of the KCNQ1 gene. The deleted region contains >90% of protein-coding part of the last exon as well as part of 3’ Untranslated Region (3’UTR) of the KCNQ1 gene. The resultant predicted protein product would lack the last seventy-three amino acid residues (>10% of the protein) and would include 27 out-of-frame residues (c.1812_*143del, p.(Gln604_Ser676delins(27))). Although this genomic deletion has not been reported previously in the literature or in the population databases, other frameshift variants in the last exon of KCNQ1 have been reported in the literature and ClinVar as likely pathogenic and pathogenic [ClinVar ID:53027, 928774] [PMID: 10024302, 16981927, 19716085, 19825999, 23098067, 23631430, 25187895]. Furthermore, functional studies performed on a frameshift variant located in the last exon (p.Pro631fs) showed that replacing these amino acid residues with out-of-frame residues might impair cell surface expression of the protein due to retention in the endoplasmic reticulum [PMID:19825999]. Based on the available evidence, this inherited c.1812_*143del variant is reported as Likely 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

There are no citations for germline classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar.

Text-mined citations for this variant ...

Record last updated Jun 23, 2024

ClinVar Genomic variation as it relates to human health

NM_000218.3(KCNQ1):c.1812_*143del (p.Gln604_Ter677delinsXaa)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...