ClinVar Miner

Submissions for variant NM_172057.2(KCNH2):c.1987G>A (p.Asp663Asn) (rs794728402)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000413178 SCV000492233 uncertain significance not specified 2016-11-29 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the KCNH2 gene. The D1003N variant has been previously reported in one Japanese individual from a cohort of individuals with acquired LQTS, who were found to have a prolonged QT interval and Torsades de Pointes ventricular tachycardia triggered by drugs, hypokalemia or bradycardia (Itoh et al., 2016). However, this individual harbored an additional cardiogenetic variant, and further clinical details and segregation studies were not described. The D1003N variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project (average read depth 7X). Furthermore, this substitution occurs at a position where amino acids with similar properties to Aspartic acid are tolerated across species, and D1003N is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. Nevertheless, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Invitae RCV000631725 SCV000752813 uncertain significance Long QT syndrome 2017-10-19 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with asparagine at codon 1003 of the KCNH2 protein (p.Asp1003Asn). The aspartic acid residue is moderately 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 observed in an individual affected with acquired long QT syndrome (LQTS), however, in that individual another LQTS associated allele was also identified (PMID: 26715165). ClinVar contains an entry for this variant (Variation ID: 373622). 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: "Possibly 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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