ClinVar Miner

Submissions for variant NM_172056.2(KCNH2):c.1262C>T (p.Thr421Met) (rs199472894)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000181785 SCV000234088 likely pathogenic not provided 2017-01-03 criteria provided, single submitter clinical testing The T421M variant in the KCNH2 gene has been reported in several unrelated individuals with LQTS and it was not observed cumulatively in approximately 4,100 reference alleles (Tester D et al., 2005; Kapplinger et al., 2009; Shimizu et al., 2009). Functional studies indicate that T421M, located in the trasmembrane helical S1 domain, results in decreased potassium current due to altered gating of the potassium channels (Anderson et al., 2006; Balijepalli et al., 2012). Missense variants in nearby residues (Y420C, A422T, P426H) have been reported in association with LQTS (Stenson et al., 2014). Additionally, the NHLBI Exome Sequencing Project reports T421M was not observed in approximately 6,500 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. However, despite the fact that multiple publications describe an association between the T421M variant in the KCNH2 gene and LQTS, family history information and segregation data was not provided. In summary, the T421M variant in the KCNH2 gene is a strong candidate to be pathogenic. However, the possibility that it is a benign variant cannot be excluded.
Invitae RCV000527961 SCV000627419 uncertain significance Long QT syndrome 2017-06-14 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 421 of the KCNH2 protein (p.Thr421Met). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and methionine. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been reported in an individual with long QT syndrome (PMID: 23136156), and has been reported in at least one individual referred for long QT syndrome genetic testing (PMID: 15840476, 19716085). ClinVar contains an entry for this variant (Variation ID: 67173). This variant identified in the KCNH2 gene is located in the transmembrane S1 region of the resulting protein (PMID: 19841300, 25348405). For more information about the location of this variant, please visit www.invitae.com/KCNH2-topology. Experimental studies have shown that this missense change cannot rescue the loss of KCNH2 in a zebrafish system, and leads to abnormal trafficking and channel gating (PMID: 23303164, 23136156). In summary, this variant has uncertain impact on KCNH2 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000057880 SCV000089400 not provided Congenital long QT syndrome no assertion provided literature only This variant has been reported as associated with Long QT syndrome in the following publications (PMID:15840476;PMID:16432067;PMID:19716085). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.

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