VCV000925996.22 - ClinVar

NM_000218.3(KCNQ1):c.1456G>A (p.Ala486Thr)

Germline

Classification

criteria provided, conflicting classifications. Learn more about how ClinVar calculates review status.

Conflicting classifications of pathogenicity
Uncertain significance (6); Likely benign (1)

7 out of 8 submissions contributed to this 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.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000218.3(KCNQ1):c.1456G>A (p.Ala486Thr)

Variation ID: 925996 Accession: VCV000925996.22

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 11p15.5 11: 2662023 (GRCh38) [ NCBI UCSC ] 11: 2683253 (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	Jun 22, 2020	Feb 15, 2026	Feb 24, 2025

HGVS

Nucleotide	Protein	Molecular consequence
NM_000218.3:c.1456G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000209.2:p.Ala486Thr	missense
NM_001406836.1:c.1360G>A	NP_001393765.1:p.Ala454Thr	missense
NM_001406837.1:c.1186G>A	NP_001393766.1:p.Ala396Thr	missense
NM_001406838.1:c.916G>A	NP_001393767.1:p.Ala306Thr	missense
NM_181798.2:c.1075G>A	NP_861463.1:p.Ala359Thr	missense
NR_002728.4:n.37972C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NR_040711.2:n.1349G>A
NC_000011.10:g.2662023G>A
NC_000011.9:g.2683253G>A
NG_008935.1:g.222033G>A
NG_016178.2:g.42976C>T
LRG_1052:g.42976C>T
LRG_1052t1:n.37976C>T
LRG_287:g.222033G>A
LRG_287t1:c.1456G>A	LRG_287p1:p.Ala486Thr
LRG_287t2:c.1075G>A	LRG_287p2:p.Ala359Thr

... more HGVS ... less HGVS

Protein change

A359T, A486T, A396T, A454T, A306T

Other names

Canonical SPDI

NC_000011.10:2662022:G:A

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.

The Genome Aggregation Database (gnomAD), exomes 0.00002

Trans-Omics for Precision Medicine (TOPMed) 0.00002

Exome Aggregation Consortium (ExAC) 0.00004

The Genome Aggregation Database (gnomAD), exomes 0.00004

Links

ClinGen: CA029975 dbSNP: rs753256800 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	2022	3159
KCNQ1OT1		Little evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	1	872

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.
not provided	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Mar 5, 2021	RCV001751341.14
Cardiac arrhythmia	Uncertain significance (1)	criteria provided, single submitter	Feb 24, 2025	RCV001841033.13
Atrial fibrillation, familial, 3 Beckwith-Wiedemann syndrome Jervell and Lange-Nielsen syndrome 1 Long QT syndrome 1 Short QT syndrome type 2	Uncertain significance (1)	criteria provided, single submitter	Dec 3, 2021	RCV002480624.8
Long QT syndrome	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Jul 29, 2024	RCV002560015.15
Cardiovascular phenotype	Likely benign (1)	criteria provided, single submitter	May 20, 2024	RCV004619539.1
KCNQ1-related disorder	Uncertain significance (1)	no assertion criteria provided	Mar 26, 2024	RCV004733172.1

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.	Expand all rows Collapse all rows 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 (Dec 03, 2021) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Beckwith-Wiedemann syndrome Long QT syndrome 1 Long QT syndrome 1 Jervell and Lange-Nielsen syndrome 1 Atrial fibrillation, familial, 3 Short QT syndrome type 2	Fulgent Genetics, Fulgent Genetics Accession: SCV002786326.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022	Observation: 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown

Uncertain significance (Oct 29, 2019) C Contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	not provided	GeneDx Accession: SCV001987174.2 First in ClinVar: Nov 06, 2021 Last updated: Mar 04, 2023	Comment: show In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Likely benign (May 20, 2024) C Contributing to aggregate classification	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Cardiovascular phenotype	Ambry Genetics Accession: SCV005126900.1 First in ClinVar: Aug 11, 2024 Last updated: Aug 11, 2024	Comment: show This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Uncertain Significance (Jul 29, 2024) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Long QT syndrome (Autosomal dominant inheritance)	All of Us Research Program, National Institutes of Health Accession: SCV004836443.2 First in ClinVar: Apr 20, 2024 Last updated: Dec 14, 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)	Comment: show This missense variant replaces alanine with threonine at codon 486 of the KCNQ1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 9/251412 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Number of individuals with the variant: 6 Zygosity: 6 Single Heterozygotes

Uncertain significance (Feb 24, 2025) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Cardiac arrhythmia	Color Diagnostics, LLC DBA Color Health Accession: SCV001355301.4 First in ClinVar: Jun 22, 2020 Last updated: May 03, 2025	Publications: PubMed (1) PubMed: 31696929 Comment: show This missense variant replaces alanine with threonine at codon 486 of the KCNQ1 protein. Computational prediction tool is inconclusive regarding the impact of this variant on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with epilepsy (PMID: 31696929). This variant has been identified in 9/251412 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Platform type: NGS

Uncertain significance (Mar 05, 2021) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	not provided	Revvity Omics, Revvity Accession: SCV003811972.3 First in ClinVar: Mar 04, 2023 Last updated: Sep 06, 2025	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Uncertain significance (Jan 25, 2024) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Long QT syndrome	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV003021618.4 First in ClinVar: Feb 07, 2023 Last updated: Feb 15, 2026	Comment: show This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 486 of the KCNQ1 protein (p.Ala486Thr). This variant is present in population databases (rs753256800, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with KCNQ1-related conditions. ClinVar contains an entry for this variant (Variation ID: 925996). 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 not expected to disrupt KCNQ1 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Uncertain significance (Mar 26, 2024) N Not contributing to aggregate classification	no assertion criteria provided	KCNQ1-related condition	PreventionGenetics, part of Exact Sciences Accession: SCV005357954.1 First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024	Comment: show The KCNQ1 c.1456G>A variant is predicted to result in the amino acid substitution p.Ala486Thr. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.020% of alleles in individuals of South Asian descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Comment:

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Comment:

This missense variant replaces alanine with threonine at codon 486 of the KCNQ1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 9/251412 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

Comment:

This missense variant replaces alanine with threonine at codon 486 of the KCNQ1 protein. Computational prediction tool is inconclusive regarding the impact of this variant on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with epilepsy (PMID: 31696929). This variant has been identified in 9/251412 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

Comment:

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 486 of the KCNQ1 protein (p.Ala486Thr). This variant is present in population databases (rs753256800, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with KCNQ1-related conditions. ClinVar contains an entry for this variant (Variation ID: 925996). 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 not expected to disrupt KCNQ1 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Comment:

The KCNQ1 c.1456G>A variant is predicted to result in the amino acid substitution p.Ala486Thr. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.020% of alleles in individuals of South Asian descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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

Text-mined citations for rs753256800 ...

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 Apr 13, 2026