ClinVar Miner

Submissions for variant NM_172056.2(KCNH2):c.1501G>A (p.Asp501Asn) (rs199472912)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 4
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000181794 SCV000234097 pathogenic not provided 2016-12-28 criteria provided, single submitter clinical testing The Asp501Asn variant in the KCNH2 gene has been reported in association with LQTS (Jongbloed R et al., 2002; Tan H et al., 2006; Nagaoka I et al, 2008; Kapplinger J et al., 2009). Jongbloed et al. first reported Asp501Asn in a patient with LQTS and classified it as a novel, pathogenic variant. Kapplinger et al. identified Asp501Asn in two individuals with LQTS and reported it absent from at least 2,600 reference alleles. Other variants at the same codon (Asp501Gly, Asp501His) have been reported in association with LQTS, supporting the functional importance of this region of the protein. Furthermore, the NHLBI ESP Exome Variant Server reports Asp501Asn was not observed in approximately 5,000 samples from individuals of European and African American backgrounds, indicating it is not a common variant in these populations.Therefore, Asp501Asn in the KCNH2 gene is interpreted as a disease-causing variant.
Invitae RCV000467289 SCV000543437 pathogenic Long QT syndrome 2019-03-22 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with asparagine at codon 501 of the KCNH2 protein (p.Asp501Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several individuals affected with long QT syndrome (PMID: 12402336, 14998624, 17088455, 25254353). ClinVar contains an entry for this variant (Variation ID: 67208). This variant has been reported to affect KCNH2 protein function (PMID: 25254353). This variant disrupts the p.Asp501 amino acid residue in KCNH2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16414944, 19926013). This suggests that this residue is clinically-significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000618688 SCV000735804 likely pathogenic Cardiovascular phenotype 2017-11-13 criteria provided, single submitter clinical testing The p.D501N variant (also known as c.1501G>A), located in coding exon 6 of the KCNH2 gene, results from a G to A substitution at nucleotide position 1501. The aspartic acid at codon 501 is replaced by asparagine, an amino acid with highly similar properties, and is located in S3 transmembrane helix. This alteration has been reported in multiple long QT syndrome (LQTS) cohorts (Jongbloed R et al. Hum. Mutat., 2002 Nov;20:382-91; Lupoglazoff JM et al. J. Am. Coll. Cardiol., 2004 Mar;43:826-30; Tan HL et al. Circulation, 2006 Nov;114:2096-103; Nagaoka I et al. Circ. J., 2008 May;72:694-9; Kapplinger JD et al. Heart Rhythm, 2009 Sep;6:1297-303; Pundi KN et al. Heart Rhythm, 2015 Apr;12:776-81). It has also been identified in a subject with a prolonged QT interval and features of left ventricular non-compaction (Ogawa K et al. Circ. J., 2009 Nov;73:2169-72). One study suggested this variant may cause a reduction in protein trafficking (Sadrieh A et al. Nat Commun., 2014 Sept;5:5069). In addition, other alterations affecting the same amino acid, p.D501H (c.1501G>C) and p.D501G (c.1502A>G) have been reported in association with LQTS (Napolitano C et al. JAMA, 2005 Dec;294:2975-80; Shimizu W et al. J. Am. Coll. Cardiol., 2009 Nov;54:2052-62). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000057917 SCV000089437 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:12402336;PMID:14998624;PMID:18441445;PMID:19716085). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.