ClinVar Miner

Submissions for variant NM_172056.2(KCNH2):c.2360T>A (p.Ile787Asn) (rs794728387)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000181849 SCV000234152 likely pathogenic not provided 2013-04-19 criteria provided, single submitter clinical testing The Ile787Asn variant in the KCNH2 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Ile787Asn results in a semi-conservative amino acid substitution of a non-polar Isoleucine with a polar Asparagine at a position that is well conserved across species. Consequently, in silico analysis predicts Ile787Asn is damaging to the protein structure/function. Mutations in nearby residues (Arg784Trp, Gly785Ala, Glu788Asp, Arg791Trp) have been reported in association with LQTS, further supporting the functional importance of this region of the protein. Furthermore, the Ile787Asn variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations.In summary, Ile787Asn in the KCNH2 gene is a good candidate for a disease-causing mutation. The variant is found in LQT panel(s).
Invitae RCV000694640 SCV000823095 uncertain significance Long QT syndrome 2018-02-27 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with asparagine at codon 787 of the KCNH2 protein (p.Ile787Asn). The isoleucine residue is highly conserved and there is a large physicochemical difference between isoleucine and asparagine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with KCNH2-related disease. ClinVar contains an entry for this variant (Variation ID: 200428). 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 C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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