ClinVar Miner

Submissions for variant NM_181798.1(KCNQ1):c.651G>A (p.Ala217=) (rs1800171)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000045941 SCV000073954 pathogenic Long QT syndrome 2018-11-15 criteria provided, single submitter clinical testing This sequence change affects codon 344 of the KCNQ1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the KCNQ1 protein. It also falls at the last nucleotide of exon 7 of the KCNQ1 coding sequence. This variant is not present in population databases (rs1800171, ExAC no frequency). This sequence change has been reported in the literature in individuals and families affected with long QT syndrome and Jervell and Lange-Nielsen syndrome (PMID: 9654228, 21810471, 9799083, 10973849, 22629021). ClinVar contains an entry for this variant (Variation ID: 3135). An experimental study evaluating the effect of this sequence change on splicing has shown that this change resulted in skipping of exon 7 in almost half of KCNQ1 mRNA generated  (PMID: 21810471). In summary, this sequence change has been reported in multiple individuals affected with long QT syndrome and Jervell and Lange-Nielsen syndrome, has been shown to segregate with disease in several families and has been shown to affect splicing of the KCNQ1 mRNA. For these reasons, this sequence change has been classified as Pathogenic.
GeneDx RCV000182159 SCV000234462 pathogenic not provided 2019-01-15 criteria provided, single submitter clinical testing The c.1032 G>A (A344A) variant in the KCNQ1 gene has been reported multiple times in association with LQTS (Kanters J et al., 1998; Murray A et al., 1999; Splawski I et al., 2000; Li H et al., 1998; Choi G et al., 2004; Struijk J et al., 2006, Kapplinger J et al., 2009). The c.1032 G>A variant changes the last nucleotide in exon 7 of the KCNQ1 gene, which affects the donor splice site and results in exons skipping (Kanters J et al., 1998; Murray A et al., 1999). The c.1032 G>A variant has been reported in several individuals with LQTS and has been shown to co-segregate with a LQTS phenotype in at least two families (Kanters J et al., 1998; Murray A et al., 1999). Considering all publications, the c.1032 G>A variant was absent from >2,600 control alleles from individuals of various ethnic backgrounds (Kanters J et al., 1998; Murray A et al., 1999; Splawski I et al., 2000; Li H et al., 1998; Choi G et al., 2004, Kapplinger J et al., 2009). In addition, a different nucleotide change at the same residue (c.1032 G>C, A344A) has also been reported to affect the donor splice site and was found to co-segregate with a LQTS phenotype in a multi-generation family (Murray A et al., 1999).
Center for Human Genetics,University of Leuven RCV000498423 SCV000579514 pathogenic Long QT syndrome 2 2017-02-09 criteria provided, single submitter clinical testing ACMG score pathogenic
Ambry Genetics RCV000621184 SCV000738084 pathogenic Cardiovascular phenotype 2017-07-07 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Confirmed de novo alteration in the setting of a new disease (appropriate phenotype) in the family
OMIM RCV000003283 SCV000023441 pathogenic Long QT syndrome 1 1999-09-07 no assertion criteria provided literature only
Institute of Medical Genetics and Genomics,Sir Ganga Ram Hospital RCV000003283 SCV000255625 pathogenic Long QT syndrome 1 2014-01-01 no assertion criteria provided research

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