VCV001782709.3 - ClinVar

NM_000218.3(KCNQ1):c.1922C>T (p.Pro641Leu)

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.

Uncertain significance

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.1922C>T (p.Pro641Leu)

Variation ID: 1782709 Accession: VCV001782709.3

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 11p15.4 11: 2847894 (GRCh38) [ NCBI UCSC ] 11: 2869124 (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	Nov 29, 2022	May 1, 2024	Nov 30, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000218.3:c.1922C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000209.2:p.Pro641Leu	missense
NM_001406836.1:c.1826C>T	NP_001393765.1:p.Pro609Leu	missense
NM_001406837.1:c.1652C>T	NP_001393766.1:p.Pro551Leu	missense
NM_001406838.1:c.1382C>T	NP_001393767.1:p.Pro461Leu	missense
NM_001406839.1:c.434C>T	NP_001393768.1:p.Pro145Leu	missense
NM_181798.2:c.1541C>T	NP_861463.1:p.Pro514Leu	missense
NR_040711.2:n.1815C>T
NC_000011.10:g.2847894C>T
NC_000011.9:g.2869124C>T
NG_008935.1:g.407904C>T
LRG_287:g.407904C>T
LRG_287t1:c.1922C>T	LRG_287p1:p.Pro641Leu
LRG_287t2:c.1541C>T	LRG_287p2:p.Pro514Leu

... more HGVS ... less HGVS

Protein change

P461L, P609L, P145L, P514L, P641L, P551L

Other names

Canonical SPDI

NC_000011.10:2847893: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

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.
Cardiovascular phenotype	Uncertain significance (1)	criteria provided, single submitter	Aug 9, 2022	RCV002410742.2
Long QT syndrome	Uncertain significance (1)	criteria provided, single submitter	Nov 30, 2023	RCV004007378.2

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.
Uncertain Significance (Nov 30, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Long QT syndrome (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	All of Us Research Program, National Institutes of Health Accession: SCV004829934.1 First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 Comment: This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more) This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)	Number of individuals with the variant: 1
Uncertain significance (Aug 09, 2022)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cardiovascular phenotype Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV002717427.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Publications: PubMed (2) PubMed: 19862833‚ 31696929 Comment: The p.P641L variant (also known as c.1922C>T), located in coding exon 16 of the KCNQ1 gene, results from a C to T substitution at nucleotide … (more) The p.P641L variant (also known as c.1922C>T), located in coding exon 16 of the KCNQ1 gene, results from a C to T substitution at nucleotide position 1922. The proline at codon 641 is replaced by leucine, an amino acid with similar properties. This alteration has been reported in a long QT syndrome cohort and an epilepsy cohort; however, clinical details were limited in both cases (Hedley PL et al. Hum Mutat, 2009 Nov;30:1486-511; Li X et al. Ann Hum Genet, 2020 03;84:161-168). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)

Comment:

The p.P641L variant (also known as c.1922C>T), located in coding exon 16 of the KCNQ1 gene, results from a C to T substitution at nucleotide position 1922. The proline at codon 641 is replaced by leucine, an amino acid with similar properties. This alteration has been reported in a long QT syndrome cohort and an epilepsy cohort; however, clinical details were limited in both cases (Hedley PL et al. Hum Mutat, 2009 Nov;30:1486-511; Li X et al. Ann Hum Genet, 2020 03;84:161-168). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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
Variant frequencies of KCNQ1, KCNH2, and SCN5A in a Chinese inherited arrhythmia cohort and other disease cohorts undergoing genetic testing.	Li X	Annals of human genetics	2020	PMID: 31696929
The genetic basis of long QT and short QT syndromes: a mutation update.	Hedley PL	Human mutation	2009	PMID: 19862833

Text-mined citations for this variant ...

Record last updated May 08, 2024

ClinVar Genomic variation as it relates to human health

NM_000218.3(KCNQ1):c.1922C>T (p.Pro641Leu)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...