ClinVar Miner

Submissions for variant NM_172057.2(KCNH2):c.1754G>T (p.Gly585Val) (rs794728398)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000181893 SCV000234196 uncertain significance not provided 2018-06-27 criteria provided, single submitter clinical testing The G925V variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The G925V variant was not observed in approximately 4000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. A non-conservative amino acid change at this position (G925R) has been reported in one individual with LQTS and was absent from 1,300 control alleles (Tester D et al., 2005). However, the G925V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Missense mutations in nearby residues (R922W, R922Q, G924E, G924A, W927R,) have been reported in association with Long QT syndrome, supporting the functional importance of this region of the protein. 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 a pathogenic mutation or a rare benign variant.
Invitae RCV000811115 SCV000951364 uncertain significance Long QT syndrome 2018-07-06 criteria provided, single submitter clinical testing This sequence change replaces glycine with valine at codon 925 of the KCNH2 protein (p.Gly925Val). The glycine residue is weakly conserved and there is a moderate physicochemical difference between glycine and valine. 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: 200497). 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.
Agnes Ginges Centre for Molecular Cardiology,Centenary Institute RCV000853468 SCV000996379 uncertain significance Sudden unexplained death 2019-06-26 criteria provided, single submitter research This variant has been identified as part of our research program. Refer to the 'condition' field for the phenotype of the proband(s) identified with this variant. For further information please feel free to contact us.

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