ClinVar Miner

Submissions for variant NM_172057.2(KCNH2):c.2235del (p.Pro746fs) (rs1064795855)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000481082 SCV000572051 likely pathogenic not provided 2017-04-28 criteria provided, single submitter clinical testing Although the c.3255delG likely pathogenic variant in the KCNH2 gene has not been reported to our knowledge, this variant causes a shift in reading frame starting at codon Proline 1086, changing it to a Leucine, and creating a premature stop codon at position 169 of the new reading frame, denoted p.Pro1086LeufsX169. This likely pathogenic variant is expected to result in the loss of the last 74 amino acids of the KCNH2 protein which are replaced by an abnormal sequence of 168 new amino acids. Other frameshift variants in the KCNH2 gene have been reported in HGMD in association with LQTS, including a frameshift variant at the same nucleotide (c.3255dupG) as well as several downstream frameshift variants (Stenson et al., 2014). Furthermore, the c.3255delG deletion was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Based on currently available evidence, c.3255delG is a strong candidate for a pathogenic variant. However, the possibility it is a rare benign variant cannot be excluded.

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