VCV000067073.19 - ClinVar

NM_000218.3(KCNQ1):c.430A>G (p.Thr144Ala)

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.

(4)

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.

Conflicting classifications of pathogenicity
Pathogenic(1); Uncertain significance(2)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000218.3(KCNQ1):c.430A>G (p.Thr144Ala)

Variation ID: 67073 Accession: VCV000067073.19

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 11p15.5 11: 2527971 (GRCh38) [ NCBI UCSC ] 11: 2549201 (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	Oct 9, 2016	Oct 8, 2024	Sep 24, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000218.3:c.430A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000209.2:p.Thr144Ala	missense
NM_001406836.1:c.430A>G	NP_001393765.1:p.Thr144Ala	missense
NM_001406837.1:c.160A>G	NP_001393766.1:p.Thr54Ala	missense
NM_001406838.1:c.430A>G	NP_001393767.1:p.Thr144Ala	missense
NM_181798.2:c.49A>G	NP_861463.1:p.Thr17Ala	missense
NR_040711.2:n.323A>G
NC_000011.10:g.2527971A>G
NC_000011.9:g.2549201A>G
NG_008935.1:g.87981A>G
LRG_287:g.87981A>G
LRG_287t1:c.430A>G	LRG_287p1:p.Thr144Ala
LRG_287t2:c.49A>G	LRG_287p2:p.Thr17Ala
	P51787:p.Thr144Ala

... more HGVS ... less HGVS

Protein change

T144A, T17A, T54A

Other names

Canonical SPDI

NC_000011.10:2527970:A:G

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

ClinGen: CA007072 UniProtKB: P51787#VAR_074936 dbSNP: rs199473451 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	1720	2663

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.
Congenital long QT syndrome	not provided (1)	no classification provided	-	RCV000057675.4
Long QT syndrome	Pathogenic (1)	criteria provided, single submitter	Nov 18, 2023	RCV000463475.13
not provided	Uncertain significance (1)	criteria provided, single submitter	Sep 24, 2024	RCV000489920.7
Cardiovascular phenotype	Uncertain significance (1)	criteria provided, single submitter	Jan 13, 2022	RCV000618499.4

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 (Jan 13, 2022)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cardiovascular phenotype Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000738071.5 First in ClinVar: Apr 14, 2018 Last updated: May 01, 2024	Comment: The c.430A>G (p.T144A) alteration is located in exon 2 (coding exon 2) of the KCNQ1 gene. This alteration results from a A to G substitution … (more) The c.430A>G (p.T144A) alteration is located in exon 2 (coding exon 2) of the KCNQ1 gene. This alteration results from a A to G substitution at nucleotide position 430, causing the threonine (T) at amino acid position 144 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. (less)
Uncertain significance (Sep 24, 2024)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000576622.7 First in ClinVar: May 22, 2017 Last updated: Oct 08, 2024	Comment: Identified independently and in conjunction with additional cardiogenetic variants, including p.(R594P), in unrelated individuals referred for LQTS genetic testing at GeneDx. Testing in some other … (more) Identified independently and in conjunction with additional cardiogenetic variants, including p.(R594P), in unrelated individuals referred for LQTS genetic testing at GeneDx. Testing in some other families was consistent with both p.(R594P) and p.(T144A) variants occurring in cis; segregation data is otherwise limited or unavailable at this time.; Not observed at significant frequency in large population cohorts (gnomAD); Functional studies demonstrated the p.(T144A) variant resulted in decreased potassium currents with slowed activation, accelerated deactivation kinetics, and/or a depolarizing shift in the voltage dependence of activation when expressed in homologous potassium channel genes (KCNQ2/3) (PMID: 23271449, 30571187); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26734131, 21152909, 19716085, 17470695, 17224687, 22581653, 23271449, 14678125, 30571187) (less)
Pathogenic (Nov 18, 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: SCV000543293.10 First in ClinVar: Apr 17, 2017 Last updated: Feb 20, 2024	Publications: PubMed (5) PubMed: 28492532‚ 14678125‚ 17470695‚ 23271449‚ 30571187 Comment: This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 144 of the KCNQ1 protein (p.Thr144Ala). … (more) This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 144 of the KCNQ1 protein (p.Thr144Ala). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with long QT syndrome (PMID: 14678125, 17470695). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 67073). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt KCNQ1 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects KCNQ1 function (PMID: 23271449, 30571187). For these reasons, this variant has been classified as Pathogenic. (less)
not provided (-)	no classification provided Method: literature only	Congenital long QT syndrome Affected status: unknown Allele origin: germline	Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust Accession: SCV000089194.3 First in ClinVar: Oct 22, 2013 Last updated: Oct 09, 2016	Publications: PubMed (5) PubMed: 22581653‚ 14678125‚ 17224687‚ 19716085‚ 17470695 Comment: This variant has been reported as associated with Long QT syndrome in the following publications (PMID:14678125;PMID:17224687;PMID:19716085;PMID:17470695). This is a literature report, and does not necessarily … (more) This variant has been reported as associated with Long QT syndrome in the following publications (PMID:14678125;PMID:17224687;PMID:19716085;PMID:17470695). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. (less)

Comment:

The c.430A>G (p.T144A) alteration is located in exon 2 (coding exon 2) of the KCNQ1 gene. This alteration results from a A to G substitution at nucleotide position 430, causing the threonine (T) at amino acid position 144 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

Comment:

Identified independently and in conjunction with additional cardiogenetic variants, including p.(R594P), in unrelated individuals referred for LQTS genetic testing at GeneDx. Testing in some other families was consistent with both p.(R594P) and p.(T144A) variants occurring in cis; segregation data is otherwise limited or unavailable at this time.; Not observed at significant frequency in large population cohorts (gnomAD); Functional studies demonstrated the p.(T144A) variant resulted in decreased potassium currents with slowed activation, accelerated deactivation kinetics, and/or a depolarizing shift in the voltage dependence of activation when expressed in homologous potassium channel genes (KCNQ2/3) (PMID: 23271449, 30571187); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26734131, 21152909, 19716085, 17470695, 17224687, 22581653, 23271449, 14678125, 30571187)

Comment:

This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 144 of the KCNQ1 protein (p.Thr144Ala). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with long QT syndrome (PMID: 14678125, 17470695). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 67073). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt KCNQ1 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects KCNQ1 function (PMID: 23271449, 30571187). For these reasons, this variant has been classified as Pathogenic.

Comment:

This variant has been reported as associated with Long QT syndrome in the following publications (PMID:14678125;PMID:17224687;PMID:19716085;PMID:17470695). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.

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
High-Throughput Functional Evaluation of KCNQ1 Decrypts Variants of Unknown Significance.	Vanoye CG	Circulation. Genomic and precision medicine	2018	PMID: 30571187
A conserved threonine in the S1-S2 loop of KV7.2 and K V7.3 channels regulates voltage-dependent activation.	Füll Y	Pflugers Archiv : European journal of physiology	2013	PMID: 23271449
Spectrum and prevalence of mutations from the first 2,500 consecutive unrelated patients referred for the FAMILION long QT syndrome genetic test.	Kapplinger JD	Heart rhythm	2009	PMID: 19716085
Clinical aspects of type-1 long-QT syndrome by location, coding type, and biophysical function of mutations involving the KCNQ1 gene.	Moss AJ	Circulation	2007	PMID: 17470695
Whole blood RNA offers a rapid, comprehensive approach to genetic diagnosis of cardiovascular diseases.	Miller TE	Genetics in medicine : official journal of the American College of Medical Genetics	2007	PMID: 17224687
Location of mutation in the KCNQ1 and phenotypic presentation of long QT syndrome.	Zareba W	Journal of cardiovascular electrophysiology	2003	PMID: 14678125

Text-mined citations for rs199473451 ...

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 08, 2024

ClinVar Genomic variation as it relates to human health

NM_000218.3(KCNQ1):c.430A>G (p.Thr144Ala)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs199473451 ...