NM_000218.3(KCNQ1):c.707T>C (p.Leu236Pro) AND Long QT syndrome

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Dec 19, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV001852301.7

Allele description [Variation Report for NM_000218.3(KCNQ1):c.707T>C (p.Leu236Pro)]

NM_000218.3(KCNQ1):c.707T>C (p.Leu236Pro)

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.707T>C (p.Leu236Pro)

Other names:

p.L236P:CTG>CCG

HGVS:

NC_000011.10:g.2572036T>C
NG_008935.1:g.132046T>C
NM_000218.3:c.707T>CMANE SELECT
NM_001406836.1:c.707T>C
NM_001406837.1:c.437T>C
NM_181798.2:c.326T>C
NP_000209.2:p.Leu236Pro
NP_000209.2:p.Leu236Pro
NP_001393765.1:p.Leu236Pro
NP_001393766.1:p.Leu146Pro
NP_861463.1:p.Leu109Pro
NP_861463.1:p.Leu109Pro
LRG_287t1:c.707T>C
LRG_287t2:c.326T>C
LRG_287:g.132046T>C
LRG_287p1:p.Leu236Pro
LRG_287p2:p.Leu109Pro
NC_000011.9:g.2593266T>C
NM_000218.2:c.707T>C
NM_181798.1:c.326T>C
NR_040711.2:n.600T>C

Protein change:

L109P

Links:

dbSNP: rs794728512

NCBI 1000 Genomes Browser:

rs794728512

Molecular consequence:

NM_000218.3:c.707T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406836.1:c.707T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406837.1:c.437T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_181798.2:c.326T>C - missense variant - [Sequence Ontology: SO:0001583]

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
SCV002213519	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Dec 19, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 29532034, 30571187, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002213519

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Dec 19, 2023)

germline

clinical testing

PubMed (3)
[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	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Mechanisms of KCNQ1 channel dysfunction in long QT syndrome involving voltage sensor domain mutations.

Huang H, Kuenze G, Smith JA, Taylor KC, Duran AM, Hadziselimovic A, Meiler J, Vanoye CG, George AL Jr, Sanders CR.

Sci Adv. 2018 Mar;4(3):eaar2631. doi: 10.1126/sciadv.aar2631.

PubMed [citation]

PMID:: 29532034
PMCID:: PMC5842040

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

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002213519.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 236 of the KCNQ1 protein (p.Leu236Pro). This variant is not present in population databases (gnomAD no frequency). 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: 200820). 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: 29532034, 30571187). 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

Last Updated: Sep 29, 2024

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