ClinVar Miner

Submissions for variant NM_172057.2(KCNH2):c.1750G>A (p.Gly584Arg) (rs794728397)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000181890 SCV000234193 uncertain significance not provided 2018-09-26 criteria provided, single submitter clinical testing The G924R variant has not been published as a mutation or been reported as a benign polymorphism to our knowledge. This variant has been previously identified at GeneDx in an individual referred for testing of LQTS. The G924R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Furthermore, this substitution occurs at a position that is conserved in mammals. Located within the cytoplasmic topological domain of the KCNH2 gene, missense mutations in the same residue as this variant (G924A, G924E) and several mutations in nearby residues (R920W, R920Q, R922W, R922Q, G925R, W927G) have been reported in the Human Gene Mutation Database in association with arrhythmia (Stenson et al., 2014), further supporting the functional importance of this residue and region of the protein. Nevertheless, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. The G924R variant was not observed in approximately 3,700 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant
Invitae RCV000701311 SCV000830105 uncertain significance Long QT syndrome 2018-01-12 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 924 of the KCNH2 protein (p.Gly924Arg). The glycine residue is weakly conserved and there is a moderate physicochemical difference between glycine and arginine. While this variant is not present in population databases, the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals with KCNH2-related disease. ClinVar contains an entry for this variant (Variation ID: 200492). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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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