ClinVar Miner

Submissions for variant NM_172056.2(KCNH2):c.2145G>A (p.Ala715=) (rs794728384)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000181840 SCV000234143 pathogenic not provided 2016-02-11 criteria provided, single submitter clinical testing The c.2145 G>A mutation in the KCNH2 gene has been previously published in multiple patients with LQTS, and was absent from at least 2,600 control alleles from individual of various ethnic backgrounds (Tester D et al., 2005; Kapplinger J et al., 2009). The G>A mutation alters the last base of exon 5, immediately 5' of the canonical “GT” of the splice donor site. In silico analysis with 3 different splice algorithms predicts that this mutation significantly reduces the quality of the splice site or even destroys the splice donor site, leading to aberrant gene splicing. Furthermore, the c.2145 G>A mutation was not observed in up to 600 control alleles of Caucasian and African American individuals tested at GeneDx, indicating it is not a common benign polymorphism in these populations. This mutation has been observed in other unrelated individuals tested for LQTS at GeneDx.In summary, c.2145 G>A in the KCNH2 gene is interpreted as a disease-causing mutation.
Invitae RCV000466148 SCV000543451 uncertain significance Long QT syndrome 2018-06-26 criteria provided, single submitter clinical testing This sequence change affects codon 715 of the KCNH2 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the KCNH2 protein. It also falls at the last nucleotide of exon 8 of the KCNH2 coding sequence. This variant is not present in population databases (rs794728384, ExAC no frequency). This variant has been reported in an individual with long QT syndrome (PMID: 19841300) as well as three individuals who were referred for long QT syndrome genetic testing (PMID: 19716085). ClinVar contains an entry for this variant (Variation ID: 200415). Nucleotide substitutions at the last nucleotide of the exon are relatively common causes of aberrant splicing (PMID: 17576681). Algorithms developed to predict the effect of nucleotide changes on mRNA splicing suggest that this variant may alter mRNA splicing, but this prediction has not been confirmed by published transcriptional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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