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NM_000218.3(KCNQ1):c.905C>T (p.Ala302Val) AND Long QT syndrome

Germline classification:
Pathogenic/Likely pathogenic (4 submissions)
Last evaluated:
Dec 14, 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:
RCV000030111.10

Allele description [Variation Report for NM_000218.3(KCNQ1):c.905C>T (p.Ala302Val)]

NM_000218.3(KCNQ1):c.905C>T (p.Ala302Val)

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.905C>T (p.Ala302Val)
HGVS:
  • NC_000011.10:g.2572970C>T
  • NG_008935.1:g.132980C>T
  • NM_000218.3:c.905C>TMANE SELECT
  • NM_001406836.1:c.905C>T
  • NM_001406837.1:c.635C>T
  • NM_181798.2:c.524C>T
  • NP_000209.2:p.Ala302Val
  • NP_000209.2:p.Ala302Val
  • NP_001393765.1:p.Ala302Val
  • NP_001393766.1:p.Ala212Val
  • NP_861463.1:p.Ala175Val
  • NP_861463.1:p.Ala175Val
  • LRG_287t1:c.905C>T
  • LRG_287t2:c.524C>T
  • LRG_287:g.132980C>T
  • LRG_287p1:p.Ala302Val
  • LRG_287p2:p.Ala175Val
  • NC_000011.9:g.2594200C>T
  • NM_000218.2:c.905C>T
  • NM_181798.1:c.524C>T
  • NR_040711.2:n.798C>T
  • P51787:p.Ala302Val
Protein change:
A175V
Links:
UniProtKB: P51787#VAR_068303; dbSNP: rs193922365
NCBI 1000 Genomes Browser:
rs193922365
Molecular consequence:
  • NM_000218.3:c.905C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406836.1:c.905C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406837.1:c.635C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_181798.2:c.524C>T - missense variant - [Sequence Ontology: SO:0001583]
Observations:
3

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
SCV000052766Women's Health and Genetics/Laboratory Corporation of America, LabCorp
no assertion criteria provided
Pathogenic
(Apr 3, 2015) 		germlineclinical testing

SCV001224616Invitae
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Pathogenic
(Dec 14, 2023) 		germlineclinical testing

PubMed (5)
[See all records that cite these PMIDs]

SCV003931250GenomeConnect - Brain Gene Registry
no classification provided
not providedunknownphenotyping only

SCV004814315All of Us Research Program, National Institutes of Health
criteria provided, single submitter

(ACMG Guidelines, 2015)		Likely Pathogenic
(Jun 26, 2023) 		germlineclinical testing

PubMed (11)
[See all records that cite these PMIDs]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown3not providednot provided108544not providedclinical testing
not providedunknownunknown1not providednot provided1not providedphenotyping only

Citations

PubMed

IKs Gain- and Loss-of-Function in Early-Onset Lone Atrial Fibrillation.

Steffensen AB, Refsgaard L, Andersen MN, Vallet C, Mujezinovic A, Haunsø S, Svendsen JH, Olesen SP, Olesen MS, Schmitt N.

J Cardiovasc Electrophysiol. 2015 Jul;26(7):715-23. doi: 10.1111/jce.12666. Epub 2015 May 4.

PubMed [citation]
PMID:
25786344

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):240-242.

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818
See all PubMed Citations (13)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000052766.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Invitae, SCV001224616.5

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (5)

Description

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 302 of the KCNQ1 protein (p.Ala302Val). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with Jervell and Lange-Nielsen syndrome and/or long QT syndrome (PMID: 17905336, 25786344, 27917693). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 36439). 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: 19808498, 25786344). For these reasons, this variant has been classified as Pathogenic.

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

From GenomeConnect - Brain Gene Registry, SCV003931250.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedphenotyping onlynot provided

Description

Variant classified as not provided and reported on 05-21-2020 by GeneDx. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator Dr. Philip Payne from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknown1not providednot provided1not providednot providednot provided

From All of Us Research Program, National Institutes of Health, SCV004814315.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided3not providednot providedclinical testing PubMed (11)

Description

This missense variant replaces alanine with valine at codon 302 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). This variant is found within a highly conserved pore-forming region. Rare nontruncating variants in this region have been shown to be significantly overrepresented in individuals with long QT syndrome (PMID: 32893267). A functional study has shown that this variant causes a significant reduction in channel currents (PMID: 19808498). This variant has been observed in compound heterozygous state with a known pathogenic KCNQ1 variant in an individual affected with autosomal recessive Jervell and Lange-Nielsen syndrome (PMID: 27917693), indicating that this variant contributes to disease. This variant has also been reported in heterozygous state in several individuals affected with or suspected of having Long QT syndrome (PMID: 15840476, 17905336, 22456477, 24606995), in an individual affected with sudden explained death (PMID: 15466642), Addisons disease with prolonged QTc interval (PMID: 22311567), or atrial fibrillation case (PMID: 24144883). This variant has been identified in 1/249650 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknown108544not providednot provided3not providednot providednot provided

Last Updated: Apr 20, 2024