ClinVar Miner

Submissions for variant NM_181798.1(KCNQ1):c.96+5G>A (rs397508111)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000046061 SCV000074074 pathogenic Long QT syndrome 2018-12-17 criteria provided, single submitter clinical testing This sequence change falls in intron 2 of the KCNQ1 mRNA. It does not directly change the encoded amino acid sequence of the KCNQ1 protein. This variant is present in population databases (rs397508111, ExAC<0.01%). This variant has been reported in the literature in individuals affected with long QT syndrome or prolonged QT interval (PMID: 10560595, 10973849, 16922724, 22429796). and in one individual affected with Jervell and Lange-Nielsen syndrome (JLNS), although in this case it co-occurred with a deleterious variant in KCNQ1 (PMID: 23392653). This variant is also known in the literature as c.639+5G>A, IVSI+5G>A, IVS2+5G>A, and M159sp. ClinVar contains an entry for this variant (Variation ID: 53047). Nucleotide substitutions within the consensus splice site are relatively common causes of aberrant splicing (PMID: 17576681, 9536098) but according to multiple splice site algorithms this particular variant is not predicted to significantly affect splicing. These predictions have not been confirmed by published functional studies. One experimental study has shown that this missense change causes a splicing defect that creates a premature termination codon (PTC) that likely results in an absent or truncated protein product ( For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000182254 SCV000234557 pathogenic not provided 2018-08-16 criteria provided, single submitter clinical testing The c.477+5 G>A pathogenic variant in the KCNQ1 gene has been published in multiple individuals with LQTS or Jervell and Lange-Nielsen syndrome (JLNS) (Ackerman et al., 1999; Chouabe et al., 2000; Tester et al., 2005; Millat et al., 2006; Kapplinger et al., 2009; Hofman et al., 2011; Crehalet at al., 2012; Mitchell et al., 2012; Al-Hassnan et al., 2017). The c.477+5 G>A variant was first described in a post-mortem case of a 12 year-old female with sudden death who had two previous episodes of near-drowning (Ackerman et al., 1999). A subsequent study identified this variant in an individual with JLNS who also harbored a second pathogenic missense variant in KCNQ1 (Chouabe et al., 2000). Four relatives of this individual were also heterozygous for the c.477+5 G>A variant; two of whom had prolonged QTc intervals but were otherwise asymptomatic (Chouabe et al., 2000). Additionally, the c.477+5 G>A variant has been described as a candidate founder mutation in the Dutch population (Hofman et al., 2011). This variant has also been observed in several other unrelated individuals who have been referred for LQTS genetic testing at GeneDx, and it is not observed at a significant frequency in large population cohorts (Lek et al., 2016).Multiple other downstream splice-site variants in the KCNQ1 gene, as well as a different variant affecting the same nucleotide (c.477+5 G>C), have been reported in the Human Gene Mutation Database in association with arrhythmia (Stenson et al., 2014). Of note, Crehalet et al. (2012) reported that all splice algorithms predicted c.477+5 G>A has a severe impact on splicing with a strong decrease in the natural splice donor site and the potential use of a cryptic donor site. In vitro mini-gene splice assays were utilized to confirm that this variant results in the use of a cryptic donor site such that the mutant transcript encodes the first 159 amino acids followed by 4 aberrant amino acids and a premature termination codon (Crehalet et al., 2012). This aberrant mRNA is likely to be degraded by nonsense-mediated mRNA decay causing a complete loss of function from this allele (Crehalet et al., 2012).
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000506366 SCV000604065 pathogenic not specified 2017-01-03 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000826192 SCV000967742 pathogenic Romano-Ward syndrome 2018-02-15 criteria provided, single submitter clinical testing The c.477+5G>A variant in KCNQ1 has been reported in the heterozygous state in > 5 individuals with Long QT syndrome (LQTS), and in the compound heterozygous sta te in one individual with Jervell and Lange-Nielsen syndrome (JLNS; Ackerman 199 9, Chouabe 2000, Hofman 2011, Crehalet 2012, Obeyesekere 2012). It segregated wi th prolonged QT-intervals in at least 3 relatives from 2 different families, inc luding that of the individual with JNLS (Ackerman 1999, Chouabe 2000). At least two relatives who were heterozygous carriers of this variant were clinically asy mptomatic for LQTS, suggesting reduced penetrance (Chouabe 2000). The c.477+5G>A variant has also been reported by other clinical laboratories in ClinVar (Varia tion ID: 53047). In addition, it has been identified in 1/30782 South Asian chr omosomes and 2/111700 European chromosomes by the Genome Aggregation Database (g nomAD,; dbSNP rs397508111). This variant is lo cated in the 5' splice region. Functional studies using patient cDNA have shown that the c.477+5G>A variant impacts splicing (Chouabe 2000, Crehalet 2012), lead ing to an aberrant mRNA transcript that is predicted to encode the first 159 ami no acids of the protein, followed by 4 aberrant residues and a premature termina tion codon. This would likely result in an absent protein. Loss-of-function vari ants in KCNQ1 are associated with LQTS (also known as Romano-Ward syndrome) in t he heterozygous state and with JLNS in the compound heterozygous or homozygous s tate. In summary, this variant meets criteria to be classified as pathogenic for LQTS in an autosomal dominant manner based upon presence in multiple affected i ndividuals, segregation studies, predicted impact to the protein, and functional studies. ACMG/AMP Criteria applied (Richards 2015): PVS1, PM2, PS4_Moderate, PP 1_Supporting.
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV000851189 SCV000993435 pathogenic Long QT syndrome 1 2019-05-23 criteria provided, single submitter research

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