ClinVar Miner

Submissions for variant NM_172057.2(KCNH2):c.1997del (p.Gly666fs) (rs794728504)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182063 SCV000234366 pathogenic not provided 2017-01-04 criteria provided, single submitter clinical testing The c. 3017delG mutation was published in three individuals in a study aimed to compare the presence of microvoltage T wave alternans, a possible indicator of arrhythmic vulnerability, in patients with LQTS versus controls (Nemec et al., 2003). Due to the nature of the study specific clinical and family history data was not provided. This mutation causes a shift in reading frame starting at codon Glycine 1006, changing it to an Alanine, and creating a premature stop codon at position 51 of the new reading frame, denoted p.Gly1006AlafsX51. This mutation is expected to result in either an abnormal, truncated protein product or loss of protein from this allele through nonsense-mediated mRNA decay. Other frameshift mutations in the KCNH2 gene have been reported in association with LQTS. Additionally, the c.3017delG variant was not observed in approximately 6,200 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In summary, c.3017delG in the KCNH2 gene is interpreted as a disease-causing mutation.
Invitae RCV000461198 SCV000543476 pathogenic Long QT syndrome 2017-11-15 criteria provided, single submitter clinical testing This sequence change deletes 1 nucleotide from exon 13 of the KCNH2 mRNA (c.3017delG), causing a frameshift at codon 1006. This creates a premature translational stop signal (p.Gly1006Alafs*51) and is expected to result in an absent or disrupted protein product. Loss-of-function variants in KCNH2 are known to be pathogenic (PMID: 19862833). This particular variant has been reported in the literature (PMID: 12877697, 15840476). This variant identified in the KCNH2 gene is located in the cytoplasmic C-terminal region of the resulting protein (PMID: 19841300, 25348405). For these reasons, this variant has been classified as Pathogenic.

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