NM_000218.3(KCNQ1):c.724G>A (p.Asp242Asn) AND not provided

Clinical significance:Pathogenic (Last evaluated: Apr 12, 2018)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000182103.7

Allele description [Variation Report for NM_000218.3(KCNQ1):c.724G>A (p.Asp242Asn)]

NM_000218.3(KCNQ1):c.724G>A (p.Asp242Asn)

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.724G>A (p.Asp242Asn)
Other names:
p.D242N:GAC>AAC
HGVS:
  • NC_000011.10:g.2572053G>A
  • NG_008935.1:g.132063G>A
  • NM_000218.2:c.724G>A
  • NM_000218.3:c.724G>AMANE SELECT
  • NM_181798.1:c.343G>A
  • NM_181798.1:c.343G>A
  • NP_000209.2:p.Asp242Asn
  • NP_000209.2:p.Asp242Asn
  • NP_861463.1:p.Asp115Asn
  • NP_861463.1:p.Asp115Asn
  • LRG_287t1:c.724G>A
  • LRG_287t2:c.343G>A
  • LRG_287t2:c.343G>A
  • LRG_287:g.132063G>A
  • LRG_287p1:p.Asp242Asn
  • LRG_287p2:p.Asp115Asn
  • LRG_287p2:p.Asp115Asn
  • NC_000011.9:g.2593283G>A
  • NC_000011.9:g.2593283G>A
  • P51787:p.Asp242Asn
Protein change:
D115N
Links:
UniProtKB: P51787#VAR_008940; dbSNP: rs199472712
NCBI 1000 Genomes Browser:
rs199472712
Molecular consequence:
  • NM_000218.2:c.724G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_000218.3:c.724G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_181798.1:c.343G>A - missense variant - [Sequence Ontology: SO:0001583]
Observations:
10

Condition(s)

Identifiers:
MedGen: CN517202

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000234406GeneDxcriteria provided, single submitter
Pathogenic
(Apr 12, 2018)
germlineclinical testing

Citation Link,

SCV000280161Stanford Center for Inherited Cardiovascular Disease, Stanford Universityno assertion criteria providedLikely pathogenic
(Jan 20, 2014)
germlineclinical testing

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing
not providedgermlinenot provided10not providednot providednot providednot providedclinical testing

Details of each submission

From GeneDx, SCV000234406.13

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

The D242N pathogenic variant in the KCNQ1 gene has been reported in association with LQTS (Itoh et al., 1998; Splawski et al., 2000; Moss et al., 2007; Jons et al., 2009; Tester et al., 2005). Furthermore, functional studies demonstrate that channels with the D242N variant have reduced current compared to the wild type channels (Mousavi Nik et al., 2015). Located within the S4 helical voltage-sensor region of the KCNQ1 gene, this variant results in a semi-conservative amino acid substitution at a position that is not conserved across species. A variant in the same residue (D242Y) and in nearby residues (R243C, R243H) have been reported in HGMD in association with LQTS (Stenson et al., 2014), further supporting the functional importance of this residue and this region of the protein. Finally, the D242N variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server).

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

From Stanford Center for Inherited Cardiovascular Disease, Stanford University, SCV000280161.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided10not providednot providedclinical testingnot provided

Description

Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. KCNQ1 p.Asp242Asn Given the case data, absence in controls, and other disease-associated variants at the same and nearby residues, we consider this variant likely disease causing. The variant has been seen in at least nine unrelated cases who underwent LQTS sequencing and likely had LQTS, including two with clear reported LQTS. There is at least weak segregation in one family. Itoh et al (1998) observed the variant in one of 31 Japanese probands with long QT syndrome who underwent analysis of KCNQ1. The authors note that the variant cosegregated with disease but no specifics are provided. Splawski et al (2000) observed the variant in 1 of 262 unrelated patients with long QT who underwent analysis of KCNQ1, KCNH2, SCN5A, KCNE1, KCNE2. Patients were ascertained in Europe and North America (may overlap with reports by Priori's group, the US long QT registry, the international long QT registry). No ancestry, segregation, or individual phenotype data was provided. Tester et al (2005) observed the variant in 1 of 541 cases. This publication is a compendium of variants identified in cases referred to Dr. Ackerman's research lab for long QT genetic testing. No individual clinical or segregation data was provided. Of note when considering this paper, it is likely that ~25% of patients in this cohort did not actually have long QT syndrome (based on the reported yield). The variant was reported in 4 individuals in the Familion compendium, which includes 2500 patients referred for clinical long QT genetic testing (Kapplinger et al 2009). Those cases likely overlap with the data in Kapa et al (2009) and Giudicessi et al (2012) since these are all from Ackerman's group and use data from his cohort and from the Familion cohort. Of note in considering the cases reported by Kapplinger et al (2009) is the lack of phenotypic data on this cohort, the low yield of 36% (vs. 70% in cohorts with firm diagnoses of long QT), and the lack of clarity regarding which variants were seen with another variant (9% of the cohort had multiple variants). The variant was reported in 3 (possibly related) long QT patients included in a study on genotype-phenotype correlations in KCNQ1 (Moss et al 2007). This study included 600 carriers of KCNQ1 variants from 101 families. Subjects were "drawn from the US portion of the International LQTS Registry (n¡425), the Netherlands’ LQTS Registry (n¡93), and the Japanese LQTS Registry (n¡82)" so there may be overlap with other publications from those groups. Given that and the author list, it is likely these cases are redundant with prior reports and with a later similar paper by the same group (Jons et al 2009). The variant was also reported by Lieve et al (2013) in 2 of 855 consecutive unrelated patients referred to GeneDx for long QT syndrome genetic testing (which included sequencing of KCNQ1, KCNH2, SCN5A, ANK2, KCNE1, KCNE2, CACNA1C, KCNJ2, CAV3, and SCN4B). Their overall yield was 30%, suggesting that less than half of the tested individuals had long QT syndrome. Other variants have been reported in association with disease at this codon (Asp242Tyr (Jons et al 2009, Lieve et al 2013)) and nearby codons (p.V241G (Kapplinger et al 2009), R243C(>10 publications), R243P(Kapplinger et al 2009), R243S (Jons et al 2009). The variant is in the S4-S5 loop (Tester et al 2005). The variant was reported online in 1 of 57,641 individuals in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of July 16, 2015). Specifically, the variant was observed in 1 of 31,876. The phenotype of that individual is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. Note that other variants with strong evidence for pathogenicity have been seen at similar frequencies in datasets like this so this does not necessarily rule out pathogenicity (Pan et al 2012).

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot provided10not providednot providednot provided

Last Updated: Oct 25, 2021

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