ClinVar Miner

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

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Total submissions: 4
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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 2016-11-03 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 individuals affected with long QT syndrome (PMID: 12402336, 14998624, 17088455, 25254353). This variant identified in the KCNH2 gene is located in the transmembrane S3 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 affects protein trafficking (PMID: 25254353). A different missense substitution at this codon (p.Asp501His) has been determined to be pathogenic (PMID: 16414944, 19926013). This suggests that the aspartic acid residue is critical for KCNH2 protein function and that other missense substitutions at this position may also be pathogenic. In summary, this is a rare missense change that is absent from population databases, has been reported in several affected individuals, and affects protein trafficking. 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 Lines of evidence used in support of classification: Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Rarity in general population databases (dbsnp, esp, 1000 genomes),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
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.

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