NM_000218.3(KCNQ1):c.1190G>A (p.Arg397Gln) AND Long QT syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Dec 20, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV001320930.7

Allele description [Variation Report for NM_000218.3(KCNQ1):c.1190G>A (p.Arg397Gln)]

NM_000218.3(KCNQ1):c.1190G>A (p.Arg397Gln)

Gene:

KCNQ1:potassium voltage-gated channel subfamily Q member 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

11p15.5

Genomic location:

Preferred name:

NM_000218.3(KCNQ1):c.1190G>A (p.Arg397Gln)

HGVS:

NC_000011.10:g.2587631G>A
NG_008935.1:g.147641G>A
NM_000218.3:c.1190G>AMANE SELECT
NM_001406836.1:c.1094G>A
NM_001406837.1:c.920G>A
NM_001406838.1:c.650G>A
NM_181798.2:c.809G>A
NP_000209.2:p.Arg397Gln
NP_000209.2:p.Arg397Gln
NP_001393765.1:p.Arg365Gln
NP_001393766.1:p.Arg307Gln
NP_001393767.1:p.Arg217Gln
NP_861463.1:p.Arg270Gln
NP_861463.1:p.Arg270Gln
LRG_287t1:c.1190G>A
LRG_287t2:c.809G>A
LRG_287:g.147641G>A
LRG_287p1:p.Arg397Gln
LRG_287p2:p.Arg270Gln
NC_000011.9:g.2608861G>A
NM_000218.2:c.1190G>A
NM_181798.1:c.809G>A
NR_040711.2:n.1083G>A

Protein change:

R217Q

Links:

dbSNP: rs374090960

NCBI 1000 Genomes Browser:

rs374090960

Molecular consequence:

NM_000218.3:c.1190G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406836.1:c.1094G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406837.1:c.920G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406838.1:c.650G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_181798.2:c.809G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Long QT syndrome (LQTS)
Identifiers:: MONDO: MONDO:0002442; MeSH: D008133; MedGen: C0023976

Recent activity

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Homo sapiens family with sequence similarity 185 member A (FAM185A), transcript ...
Homo sapiens family with sequence similarity 185 member A (FAM185A), transcript variant 13, non-coding RNA
gi|1890608812|ref|NR_146984.3|

Nucleotide
JGI_CAAP1463.rev NIH_XGC_tropInt1 Xenopus tropicalis cDNA clone IMAGE:7710152 3'...
JGI_CAAP1463.rev NIH_XGC_tropInt1 Xenopus tropicalis cDNA clone IMAGE:7710152 3', mRNA sequence
gi|58779274|gnl|dbEST|27672666|gb|C 47.1|

Nucleotide
Hereditary neutrophilia
Hereditary neutrophilia

MedGen

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001511738	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Dec 20, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 34319147, 36136372, 25616976, 28492532
SCV004836394	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Jun 8, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 25616976, 27920829, 28749187, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001511738

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Dec 20, 2023)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

SCV004836394

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Jun 8, 2023)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	1	not provided	not provided	108544	not provided	clinical testing

Citations

PubMed

Rare Coding Variants Associated With Electrocardiographic Intervals Identify Monogenic Arrhythmia Susceptibility Genes: A Multi-Ancestry Analysis.

Choi SH, Jurgens SJ, Haggerty CM, Hall AW, Halford JL, Morrill VN, Weng LC, Lagerman B, Mirshahi T, Pettinger M, Guo X, Lin HJ, Alonso A, Soliman EZ, Kornej J, Lin H, Moscati A, Nadkarni GN, Brody JA, Wiggins KL, Cade BE, Lee J, et al.

Circ Genom Precis Med. 2021 Aug;14(4):e003300. doi: 10.1161/CIRCGEN.120.003300. Epub 2021 Jul 28.

PubMed [citation]

PMID:: 34319147
PMCID:: PMC8373440

Prevalence and Phenotypic Burden of Monogenic Arrhythmias Using Integration of Electronic Health Records With Genetics.

Nafissi NA, Abdulrahim JW, Kwee LC, Coniglio AC, Kraus WE, Piccini JP, Daubert JP, Sun AY, Shah SH.

Circ Genom Precis Med. 2022 Oct;15(5):e003675. doi: 10.1161/CIRCGEN.121.003675. Epub 2022 Sep 22.

PubMed [citation]

PMID:: 36136372
PMCID:: PMC9588708

See all PubMed Citations (7)

Details of each submission

From Invitae, SCV001511738.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 397 of the KCNQ1 protein (p.Arg397Gln). This variant is present in population databases (rs374090960, gnomAD 0.004%). This missense change has been observed in individual(s) with clinical features of long QT syndrome (PMID: 25616976, 34319147, 36136372). This variant is also known as c.809G>A (p.Arg270Gln). ClinVar contains an entry for this variant (Variation ID: 372649). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on KCNQ1 protein function. Experimental studies have shown that this missense change affects KCNQ1 function (PMID: 25616976). 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From All of Us Research Program, National Institutes of Health, SCV004836394.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (4)

Description

This missense variant replaces arginine with glutamine at codon 397 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). A functional study has shown that this variant causes a reduction of channel current and impaired trafficking in transfected HEK293 cells (PMID: 25616976). This variant has been reported in an individual suspected of having long QT syndrome (PMID: 28749187) and in two individuals affected with dilated cardiomyopathy and ventricular tachycardia (PMID: 25616976, 27920829). This variant has been identified in 4/251362 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	108544	not provided	not provided		1	not provided	not provided	not provided

Last Updated: May 7, 2024

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