ClinVar Miner

Submissions for variant NM_172057.2(KCNH2):c.2040dup (p.Ser681fs) (rs864622174)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000487260 SCV000572634 likely pathogenic not provided 2017-10-26 criteria provided, single submitter clinical testing The c.3060dupC variant was identified in 5 relatives from a family referred for LQTS genetic testing (Itoh et al., 2015). However, detailed clinical information was not provided. This variant causes a shift in reading frame starting at codon serine 1021, changing it to a glutamine, and creating a premature stop codon at position 98 of the new reading frame, denoted p.Ser1021GlnfsX98. Because the new termination codon is located in the last exon, nonsense-mediated mRNA decay is not expected. This variant is expected to result in an abnormal, truncated protein product, in which the last 139 amino acids are replaced by 97 different amino acids. It is not known whether this abnormal protein is stable or, if stable, what the precise effect is of this variant. However, multiple other downstream frameshift variants in the KCNH2 gene have been reported in Human Gene Mutation Database in association with LQTS (Stenson et al., 2014), suggesting loss of function as a mechanism of disease. Lastly, data from control individuals in publicly available databases is not available to assess the frequency of c.3060dupC in the general population.

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