ClinVar Miner

Submissions for variant NM_181798.1(KCNQ1):c.870+2T>C (rs794728528)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182182 SCV000234485 likely pathogenic not provided 2016-11-08 criteria provided, single submitter clinical testing The c.1251+2 T>C likely pathogenic variant in the KCNQ1 gene has been previously reported in one individual referred for LQTS genetic testing, and was not detected in 2,600 control alleles of diverse ethnic backgrounds (Kapplinger et al., 2009). Additionally, c.1251+2 T>C was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, nor was it observed in the Exome Aggregation Consortium (ExAC), indicating it is not a common benign variant in these populations. This variant destroys the canonical splice donor site in intron 9 of the KCNQ1 gene and is predicted to cause abnormal gene splicing. In silico splicing algorithms predict this variant causes in-frame skipping of adjacent exon 9, which may affect protein stability since it spans a transmembrane region. Moreover, other cannonical splice site variants in the KCNQ1 gene have been reported in HGMD in association with LQTS (Stenson et al., 2014). Nevertheless, in the absence of functional mRNA studies, the physiological consequence of the c.1251+2 T>C variant cannot be precisely determined.
Color Health, Inc RCV001524185 SCV001733963 likely pathogenic Arrhythmia 2020-08-04 criteria provided, single submitter clinical testing This variant causes a T to C nucleotide substitution at the +2 position of intron 9 of the KCNQ1 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. This variant is likely to cause an in-frame skipping of exon 9 (123 bp-long). Multiple pathogenic missense variants have been reported in this exon (Clinvar), indicating the functional and clinical importance of the region that may be affected by this variant. Although functional studies have not been reported, this variant is expected to result in a disrupted protein product and impair KCNQ1 channel function. This variant has been reported in one individual referred for the long QT syndrome genetic test (PMID: 19716085). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of KCNQ1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic.

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