NM_000218.3(KCNQ1):c.448G>A (p.Ala150Thr) AND Long QT syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Jan 9, 2024
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:: RCV000803828.15

Allele description [Variation Report for NM_000218.3(KCNQ1):c.448G>A (p.Ala150Thr)]

NM_000218.3(KCNQ1):c.448G>A (p.Ala150Thr)

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.448G>A (p.Ala150Thr)

HGVS:

NC_000011.10:g.2527989G>A
NG_008935.1:g.87999G>A
NM_000218.3:c.448G>AMANE SELECT
NM_001406836.1:c.448G>A
NM_001406837.1:c.178G>A
NM_001406838.1:c.448G>A
NM_181798.2:c.67G>A
NP_000209.2:p.Ala150Thr
NP_000209.2:p.Ala150Thr
NP_001393765.1:p.Ala150Thr
NP_001393766.1:p.Ala60Thr
NP_001393767.1:p.Ala150Thr
NP_861463.1:p.Ala23Thr
NP_861463.1:p.Ala23Thr
LRG_287t1:c.448G>A
LRG_287t2:c.67G>A
LRG_287:g.87999G>A
LRG_287p1:p.Ala150Thr
LRG_287p2:p.Ala23Thr
NC_000011.9:g.2549219G>A
NM_000218.2:c.448G>A
NM_181798.1:c.67G>A
NR_040711.2:n.341G>A

Protein change:

A150T

Links:

dbSNP: rs794728577

NCBI 1000 Genomes Browser:

rs794728577

Molecular consequence:

NM_000218.3:c.448G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406836.1:c.448G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406837.1:c.178G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406838.1:c.448G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_181798.2:c.67G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000943715	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 9, 2024)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 29532034, 30571187, 31899541, 28492532
SCV004838745	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] 3189954, 29532034, 31899541, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000943715

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jan 9, 2024)

germline

clinical testing

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

SCV004838745

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	2	not provided	not provided	108544	not provided	clinical testing

Citations

PubMed

High-Throughput Functional Evaluation of KCNQ1 Decrypts Variants of Unknown Significance.

Vanoye CG, Desai RR, Fabre KL, Gallagher SL, Potet F, DeKeyser JM, Macaya D, Meiler J, Sanders CR, George AL Jr.

Circ Genom Precis Med. 2018 Nov;11(11):e002345. doi: 10.1161/CIRCGEN.118.002345.

PubMed [citation]

PMID:: 30571187
PMCID:: PMC6309341

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

See all PubMed Citations (6)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000943715.4

#	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 alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 150 of the KCNQ1 protein (p.Ala150Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of long QT syndrome (PMID: 31899541). ClinVar contains an entry for this variant (Variation ID: 200909). 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%. Experimental studies have shown that this missense change affects KCNQ1 function (PMID: 29532034, 30571187, 31899541). 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, SCV004838745.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	not provided	clinical testing	PubMed (4)

Description

This missense variant replaces alanine with threonine at codon 150 of the KCNQ1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Functional studies have shown that this variant causes a reduction of potassium channel current in transfected cells (PMID: 29532034, 3189954). This variant has been reported in an individual affected with long QT syndrome (PMID: 31899541). This variant has not been identified 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		2	not provided	not provided	not provided

Last Updated: Nov 10, 2024

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