ClinVar Miner

Submissions for variant NM_172057.2(KCNH2):c.1765dup (p.Glu589fs) (rs794728458)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000181996 SCV000234299 uncertain significance not provided 2016-08-18 criteria provided, single submitter clinical testing The c.2785dupG variant of uncertain significance in the KCNH2 gene has been previously reported in one individual from a cohort of 541 individuals with suspected LQTS (denoted as ins G 2785-2786 or G928fs/10 in this study), and was absent from 1,488 reference alleles (Tester et al., 2005). It has also been observed in one other individual referred for LQTS genetic testing at GeneDx. However, observation in these two individuals, for whom clinical, family history, and segregation details are lacking, is not sufficient to determine the absolute pathogenicity of this variant. Additionally, data from control individuals in the NHLBI Exome Sequencing Project and Exome Aggregation Consortium lacked sufficient coverage to assess whether c.2785dupG may be a common benign variant in the general population. Nevertheless, this variant causes a shift in reading frame starting at codon Glutamic acid 929, changing it to a Glycine, and creating a premature stop codon at position 11 of the new reading frame, denoted p.Glu929GlyfsX11. This variant is expected to result in either an abnormal, truncated protein product or loss of protein from this allele through nonsense-mediated mRNA decay. Furthermore, multiple other frameshift variants in the KCNH2 gene have been reported in HGMD in association with LQTS (Stenson et al., 2014). Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Invitae RCV000698798 SCV000827484 pathogenic Long QT syndrome 2018-05-17 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Glu929Glyfs*11) in the KCNH2 gene. It is expected to result in an absent or disrupted protein product. While this variant is not present in population databases, the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been observed in an individual referred for testing for long QT syndrome (LQTS) (PMID: 15840476). This variant is also described as ins G 2785-2786 (G928fs/10*) in the literature. ClinVar contains an entry for this variant (Variation ID: 200678). Loss-of-function variants in KCNH2 are known to be pathogenic (PMID: 19862833). For these reasons, this variant has been classified as Pathogenic.

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