ClinVar Miner

Submissions for variant NM_172056.2(KCNH2):c.1468G>A (p.Ala490Thr) (rs28928905)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182022 SCV000234325 pathogenic not provided 2012-01-23 criteria provided, single submitter clinical testing The Ala490Thr mutation in the KCNH2 gene has been reported multiple times in association with LQTS. Zhang et al. (2008) reported that Ala490Thr co-segregated with a prolonged or borderline QT interval in a family with seven affected individuals from three generations. Kapplinger et al. (2009) also reported Ala490Thr was present in a single individual referred for LQTS testing and was absent from approximately 2600 control alleles. Finally, Oka et al. (2010) reported Ala490Thr in a 27 year-old female with severe bradycardia due to Torsades de Pointes induced by atrioventricular block and a QTc interval of 600ms. In addition, functional studies by Oka et al. (2010) showed Ala490Thr caused voltage gate dysfunction of the potassium channel. Furthermore, the NHLBI ESP Exome Variant Server reports Ala490Thr was not observed in approximately 5,000 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. Finally, mutations in the same codon (Ala490Pro) and surrounding codons (Ile489Phe, His492Tyr) have been reported in association with LQTS, further supporting the functional importance of this residue and this region of the protein. The variant is found in LQT panel(s).
Invitae RCV000703745 SCV000832659 pathogenic Long QT syndrome 2018-12-07 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 490 of the KCNH2 protein (p.Ala490Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with long QT syndrome (PMID: 20975234, 18808722). ClinVar contains an entry for this variant (Variation ID: 14430). Experimental studies have shown that this missense change causes a reduction in the current density and re-polarization of the potassium channels (PMID: 23303164, 20975234, 11170080). For these reasons, this variant has been classified as Pathogenic.
Human Genome Sequencing Center Clinical Lab,Baylor College of Medicine RCV000709729 SCV000839967 pathogenic Long QT syndrome 2 2018-03-07 criteria provided, single submitter clinical testing The c.1468G>A (p.Ala490Thr) variant in the KCNH2 has been identified in at least four unrelated individuals with long QT syndrome (LQTS) (PMIDs: 11170080, 18441445, 18808722, 19716085) and has been found to co-segregate with LQTS (PMID 18808722). This variant was observed de novo in a proband with LQTS (PMID 11170080). This variant is absent from public databases, occurs at a position where a different change(p.A490P) have been shown to segregate with LQTS in a large family with 100% penetrance, located in a functional domain where pathogenic variants have been identified and predicted to be damaging by multiple algorithms. Additionally two independent functional studies implicate this variant to result in loss of channel function (PMIDs 11170080 and 20975234). Therefore, this variant is classified as a pathogenic variant in accordance with ACMG guidelines.
OMIM RCV000015511 SCV000035776 pathogenic Long QT syndrome, bradycardia-induced 2001-02-01 no assertion criteria provided literature only
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000057910 SCV000089430 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:11170080;PMID:18441445;PMID:18808722;PMID:19716085;PMID:20975234). 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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