ClinVar Miner

Submissions for variant NM_172056.2(KCNH2):c.453dup (p.Thr152fs) (rs761863251)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000599277 SCV000709874 pathogenic not provided 2018-10-21 criteria provided, single submitter clinical testing The c.453dupC pathogenic variant in the KCNH2 gene has been previously reported in multiple individuals in association with LQTS (Splawski et al., 2000; Tester et al., 2005; Millat et al., 2006; Kapplinger et al., 2009; Itoh et al., 2016). Additionally, the c.453dupC variant was recently identified in one Spanish family of African ancestry, and while multiple cardiogenetic variants were identified in this family, only c.453dupC segregated with LQTS in all three affected siblings within this family (Caballero et al., 2017). The c.453dupC variant has been observed in 15/66246 (0.02%) alleles from individuals of Non-Finnish European ancestry, and in 3/10234 (0.03%) alleles from individuals of African ancestry in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This variant causes a shift in reading frame starting at codon threonine 152, changing it to a histidine, and creating a premature stop codon at position 180 of the new reading frame, denoted p.Thr152HisfsX180. This pathogenic 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 downstream frameshift variants in the KCNH2 gene have been reported in the Human Gene Mutation Database in association with LQTS (Stenson et al., 2014).
Invitae RCV000631596 SCV000752678 pathogenic Long QT syndrome 2018-12-31 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Thr152Hisfs*180) in the KCNH2 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs761863251, ExAC 0.03%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported to segregate with long QT syndrome in a single family (PMID: 28049825) and has been reported in several individuals with this condition (PMID: 10973849, 20851114). This variant is also known as insC453–454* (P151fs/179) and c.453dup (p.Thr152fs) in the literature. ClinVar contains an entry for this variant (Variation ID: 503669). 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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