ClinVar Miner

Submissions for variant NM_181798.1(KCNQ1):c.302+5G>A (rs397508122)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182098 SCV000234401 pathogenic not provided 2015-06-11 criteria provided, single submitter clinical testing The c.683+5 G>A mutation in KCNQ1 has been reported in three unrelated patients with LQTS and it was absent from more than 1,300 control individuals (Moss A et al., 2007; Kapa S et al., 2009). This mutation alters the splice donor site in intron 4 and is expected to cause abnormal gene splicing. This may lead to loss of protein function due to protein truncation or absence of protein from this allele due to mRNA decay. In addition, in silico analysis with 3 different splice algorithms predicts that this mutation significantly reduces the quality of the splice site. The c.683+5 G>A mutation in KCNQ1 has been observed in other unrelated individuals tested for LQTS at GeneDx. In summary, c.683+5 G>A in the KCNQ1 gene is interpreted as a disease-causing mutation. The variant is found in LQT panel(s).
Color Health, Inc RCV001176351 SCV001340315 likely pathogenic Arrhythmia 2020-08-04 criteria provided, single submitter clinical testing This variant causes a G>A nucleotide substitution at the +5 position of intron 4 of the KCNQ1 gene. An in vitro mini-gene splice assay has shown that this variant causes exon 4 skipping and premature protein truncation (Crehalet 2012). This variant has been reported in two individuals affected with long QT syndrome (PMID: 28438721, 29740400). This variant has been reported in compound heterozygosity with a pathogenic variant in individuals affected with severe phenotype (Crehalet 2012) or with autosomal recessive Jervell and Lange-Nielsen syndrome (PMID: 27917693). This variant has also been identified in 4/271744 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001255476 SCV001431894 uncertain significance not specified 2020-08-10 criteria provided, single submitter clinical testing Variant summary: KCNQ1 c.683+5G>A alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.2e-05 in 248582 control chromosomes (gnomAD and publication data). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.683+5G>A has been reported in the literature in individuals affected with LQTS and Jervell and Lange-Nielsen Syndrome (Moss_2007, Kapa_2009, Barsheshet_2012, Lieve_2013, Ruwald_2016, Wang_2016, Al-Hassnan_2017, Koponen_2018, Huttunen_2018). These reports do not provide unequivocal conclusions about association of the variant with Arrhythmia. In addition, co-occurrence with another pathogenic variant has been reported (KCNQ1 c.1484_1485delCT, p.L496AfsX19, Wang_2016), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance and pathogenic. Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae RCV001389794 SCV001591272 pathogenic Long QT syndrome 2020-10-21 criteria provided, single submitter clinical testing This sequence change falls in intron 4 of the KCNQ1 gene. It does not directly change the encoded amino acid sequence of the KCNQ1 protein. It affects a nucleotide within the consensus splice site of the intron. This variant is present in population databases (rs397508122, ExAC 0.009%). This variant has been observed in individual(s) with long QT syndrome and Jervell and Lange-Nielsen syndrome (PMID: 28438721, 27917693, 17470695, 23631430, 29622001, 19841300). It has also been observed to segregate with disease in related individuals. This variant is also known as IVS4+5G>A in the literature. ClinVar contains an entry for this variant (Variation ID: 53084). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic.

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