ClinVar Miner

Submissions for variant NM_172057.2(KCNH2):c.1939_1940del (p.Leu647fs) (rs748706373)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182004 SCV000234307 pathogenic not provided 2018-05-23 criteria provided, single submitter clinical testing The c.2959_2960delCT pathogenic variant has been published previously in association with LQTS and sudden arrhythmic death syndrome (SADS) (Kapplinger et al., 2009; Splawski et al., 2000; Nunn et al., 2011; Itoh et al., 2015). Splawski et al. (2000) initially reported this variant in 1/262 probands with a QTc greater than 460ms and/or documented torsade de pointes, ventricular fibrillation, cardiac arrest, or aborted sudden death; however, it is unclear whether additional arrhythmogenic variants were identified in this individual. Nunn et al. (2011) identified this variant in a first-degree relative of a SADS patient with a personal history of ventricular fibrillation and ICD discharge but normal QTc. This individual also harbored a variant in the KCNE1 gene. The c.2959_2960delCT variant has also been reported in three families with confirmed or suspected LQTS; however, specific clinical, family history or segregation data was not provided (Kapplinger et al., 2009; Itoh et al., 2015). The c.2959_2960delCT variant causes a shift in reading frame starting at codon Leucine 987, changing it to an Valine, and creating a premature stop codon at position 131 of the new reading frame, denoted p.Leu987ValfsX131. 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. 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). Furthermore, the c.2959_2960delCT variant 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.In summary, c.2959_2960delCT in the KCNH2 gene is interpreted as a pathogenic variant.
Ambry Genetics RCV000254145 SCV000320148 pathogenic Cardiovascular phenotype 2016-08-26 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Invitae RCV000471453 SCV000543466 pathogenic Long QT syndrome 2018-10-31 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Leu987Valfs*131) in the KCNH2 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs748706373, ExAC 0.01%). This particular variant has been reported in the literature in individuals and families affected with long QT syndrome (PMID: 10973849, 26669661), and in individuals referred for long QT testing (PMID: 23098067, 19716085). This variant is also known as p.P986fs/130 in the literature. ClinVar contains an entry for this variant (Variation ID: 200693). Loss-of-function variants in KCNH2 are known to be pathogenic (PMID: 19862833). For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000254145 SCV000696029 pathogenic Cardiovascular phenotype 2017-01-30 criteria provided, single submitter clinical testing Variant summary: The KCNH2 c.2959_2960delCT (p.Leu987Valfs) variant results in a premature termination codon, predicted to cause a truncated or absent KCNH2 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. This variant was found in 2/98624 control chromosomes at a frequency of 0.0000203, which does not exceed the estimated maximal expected allele frequency of a pathogenic KCNH2 variant (0.0001233). Multiple publications have cited the variant in affected individuals diagnosed with LQTS. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.

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