ClinVar Miner

Submissions for variant NM_181798.1(KCNQ1):c.96+1G>A (rs762814879)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182253 SCV000234556 pathogenic not provided 2018-11-02 criteria provided, single submitter clinical testing The c.477+1 G>A pathogenic variant in the KCNQ1 gene has been reported previously multiple times in association with LQTS (Splawski et al., 2000; Van Langen et al., 2003; Choi et al., 2004; Kapplinger et al., 2009). This variant has also been reported in association with Jervell and Lange-Nielsen syndrome (JLNS) in patients who are homozygous for this variant or compound heterozgyous for two variants in the KCNQ1 gene (Winbo et al., 2014; Uysal et al., 2017). Zehelein et al. (2006) observed homozygous c.477+1 G>A variants in two related individuals with JLNS; however, heterozygous carriers in this family reportedly had no cardiac symptoms. The c.477+1 G>A pathogenic variant has been observed in several unrelated individuals tested for LQTS at GeneDx. This pathogenic variant destroys the splice donor site of intron 2 and is predicted to cause abnormal gene splicing. The c.477+1 G>A variant is predicted to lead to either an abnormal message, which is subjected to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. Furthermore, the c.477+1 G>A variant is not observed in large population cohorts (Lek et al., 2016).
Invitae RCV000473506 SCV000543303 pathogenic Long QT syndrome 2016-05-20 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 2 of the KCNQ1 gene. It disrupts mRNA splicing and results in an absent or disrupted protein product. Truncating variants in KCNQ1 are known to be pathogenic (PMID: 19862833). This particular variant has been reported in several individuals affected with Jervell and Lange-Nielsen syndrome (PMID: 16987820, 22629021, 24552659) and in an individual referred for long QT syndrome testing (PMID: 19716085). ClinVar contains an entry for this variant (Variation ID: 200874). Experimental studies have shown that this intronic change leads to skipping of exon 1 and introduces a premature termination codon at exon 4 (PMID: 16987820). For these reasons, this variant has been classified as Pathogenic.
Center for Human Genetics and Laboratory Diagnostics, Dr. Klein, Dr. Rost and Colleagues RCV000678956 SCV000805171 pathogenic Long QT syndrome 1 2018-05-04 criteria provided, single submitter clinical testing

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