Submissions for variant NM_000238.4(KCNH2):c.3305C>T (p.Thr1102Ile)

dbSNP: rs794728405

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000181915	SCV000234218	uncertain significance	not provided	2018-12-10	criteria provided, single submitter	clinical testing	The T1102I variant of uncertain significance in the KCNH2 gene has not been published as pathogenic or been reported as benign to our knowledge. This variant has been identified in at least three unrelated individuals referred for arrhythmia genetic testing at GeneDx; however, two of these individuals also harbor another likely pathogenic variant. The T1102I variant is not observed in large population cohorts (Lek et al., 2016). T1102I 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. However, in-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Additional evidence is needed to clarify pathogenicity, including observation in a significant number of affected individuals, segregation data, and functional evidence.Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or benign.
Invitae	RCV001045673	SCV001209539	uncertain significance	Long QT syndrome	2024-01-04	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 1102 of the KCNH2 protein (p.Thr1102Ile). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with KCNH2-related conditions. ClinVar contains an entry for this variant (Variation ID: 200531). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The isoleucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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.
Color Diagnostics, LLC DBA Color Health	RCV001842838	SCV001347039	uncertain significance	Cardiac arrhythmia	2023-12-05	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with isoleucine at codon 1102 of the KCNH2 protein. Computational prediction tools and conservation analyses suggest that this variant may not impact the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with cardiovascular disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.