ClinVar Miner

Submissions for variant NM_172056.2(KCNH2):c.1684C>T (p.His562Tyr) (rs794728481)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182026 SCV000234329 pathogenic not provided 2012-02-24 criteria provided, single submitter clinical testing The His562Tyr mutation in the KCNH2 gene has not been reported previously as a disease-causing mutation nor as a benign polymorphism, to our knowledge. His562Tyr results in a non-conservative amino acid substitution of a positively charged Histidine with a neutral, polar Tyrosine. Located in the S5 segment of the KCNH2 gene, different mutations at the same codon (His562Arg, His562Pro) as well as mutations in nearby codons (Ala561Pro, Ala561Thr, Ala561Val, Trp563Cys, Trp563Gly) have been reported in association with LQTS, supporting the functional importance of this region of the protein. The NHLBI ESP Exome Variant Server reports His562Tyr 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. In summary, the presence of His562Tyr in the KCNH2 gene is consistent with an autosomal dominant form of LQTS. The variant is found in LQT panel(s).
Invitae RCV000531749 SCV000627431 uncertain significance Long QT syndrome 2017-08-22 criteria provided, single submitter clinical testing This sequence change replaces histidine with tyrosine at codon 562 of the KCNH2 protein (p.His562Tyr). The histidine residue is highly conserved and there is a moderate physicochemical difference between histidine and tyrosine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with a KCNH2-related disease. ClinVar contains an entry for this variant (Variation ID: 200733). This variant identified in the KCNH2 gene is located in the transmembrane S5 region of the resulting protein (PMID: 19841300, 25348405). For more information about the location of this variant, please visit www.invitae.com/KCNH2-topology. It is unclear how this variant impacts the function of this protein. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). Two different missense substitutions at this codon (p.His562Arg and p.His562Pro) have been determined to be deleterious (PMID: 25819988, 25417810 and PMID: 22949429, 16432067, 15242738). This suggests that the histidine residue is critical for KCNH2 protein function and that other missense substitutions at this position may also be deleterious. 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.

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