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NM_000218.3(KCNQ1):c.590C>T (p.Pro197Leu) AND Long QT syndrome

Germline classification:
Uncertain significance (3 submissions)
Last evaluated:
Jul 29, 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:
RCV000631621.19

Allele description [Variation Report for NM_000218.3(KCNQ1):c.590C>T (p.Pro197Leu)]

NM_000218.3(KCNQ1):c.590C>T (p.Pro197Leu)

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.590C>T (p.Pro197Leu)
Other names:
p.P197L:CCC>CTC
HGVS:
  • NC_000011.10:g.2570740C>T
  • NG_008935.1:g.130750C>T
  • NM_000218.3:c.590C>TMANE SELECT
  • NM_001406836.1:c.590C>T
  • NM_001406837.1:c.320C>T
  • NM_181798.2:c.209C>T
  • NP_000209.2:p.Pro197Leu
  • NP_000209.2:p.Pro197Leu
  • NP_001393765.1:p.Pro197Leu
  • NP_001393766.1:p.Pro107Leu
  • NP_861463.1:p.Pro70Leu
  • NP_861463.1:p.Pro70Leu
  • LRG_287t1:c.590C>T
  • LRG_287t2:c.209C>T
  • LRG_287:g.130750C>T
  • LRG_287p1:p.Pro197Leu
  • LRG_287p2:p.Pro70Leu
  • NC_000011.9:g.2591970C>T
  • NM_000218.2:c.590C>T
  • NM_181798.1:c.209C>T
  • NR_040711.2:n.483C>T
Protein change:
P107L
Links:
dbSNP: rs200108320
NCBI 1000 Genomes Browser:
rs200108320
Molecular consequence:
  • NM_000218.3:c.590C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406836.1:c.590C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406837.1:c.320C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_181798.2:c.209C>T - missense variant - [Sequence Ontology: SO:0001583]
Observations:
18

Condition(s)

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

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000752703Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Uncertain significance
(Jan 6, 2024) 		germlineclinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV004022089Dept of Medical Biology, Uskudar University
criteria provided, single submitter

(Dept of Medical Biology Variant Classification)		Uncertain significance
(Jan 8, 2024) 		unknownresearch

Citation Link,

SCV004838766All of Us Research Program, National Institutes of Health
criteria provided, single submitter

(ACMG Guidelines, 2015)		Uncertain Significance
(Jul 29, 2024) 		germlineclinical testing

PubMed (3)
[See all records that cite these PMIDs]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown18not providednot provided143475not providedclinical testing
Turkishunknownyes1not providednot providednot providednot providedresearch

Citations

PubMed

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

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
See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000752703.5

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)

Description

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 197 of the KCNQ1 protein (p.Pro197Leu). This variant is present in population databases (rs200108320, gnomAD 0.01%). 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: 191476). 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 are conflicting or provide insufficient evidence to determine the effect of this variant on 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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Dept of Medical Biology, Uskudar University, SCV004022089.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1Turkish1not providednot providedresearchnot provided

Description

Criteria: PM1, PP3

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownyesnot providednot providednot provided1not providednot providednot provided

From All of Us Research Program, National Institutes of Health, SCV004838766.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided18not providednot providedclinical testing PubMed (3)

Description

This missense variant replaces proline with leucine at codon 197 of the KCNQ1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that the mutant protein exhibits partially reduced cell surface expression but normal or increased potassium channel activity, which is inconsistent with a mutation causing long QT syndrome (PMID: 29532034, 30571187). This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 13/249032 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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknown143475not providednot provided18not providednot providednot provided

Last Updated: Jan 13, 2025