ClinVar Miner

Submissions for variant NM_000238.3(KCNH2):c.2390C>A (p.Ala797Asp) (rs794728389)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 2
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000181856 SCV000234159 likely pathogenic not provided 2013-06-12 criteria provided, single submitter clinical testing p.Ala797Asp (GCC>GAC): c.2390 C>A in exon 9 of the KCNH2 gene (NM_000238.2)The Ala797Asp variant in the KCNH2 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Ala797Asp results in a non-conservative amino acid substitution of a non-polar Alanine residue with a negatively charged Aspartic acid residue at a position that is conserved across species. In silico analysis predicts Ala797Asp is probably damaging to the protein structure/function. Mutations in nearby residues (Glu788Asp, Glu788Lys, Arg791Trp, Gly800Glu, Gly800Trp) have been reported in association with LQTS, further supporting the functional importance of this region of the protein. Furthermore, the Ala797Asp 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, while Ala797Asp is a good candidate for a disease-causing mutation, with the clinical and molecular information available at this time we cannot unequivocally determine the clinical significance of this variant. The variant is found in LQT panel(s).
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000223774 SCV000280124 uncertain significance not specified 2013-07-23 no assertion criteria provided clinical testing Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. KCNH2 p.Ala797Asp This is a novel variant, not previously reported in affected patients nor in controls. We classify it as a variant of unknown significance (VUS). This is a non-conservative amino acid change in which a nonpolar Alanine is replaced with a negatively-charged Aspartic Acid at a position that GeneDx reports is conserved across species. In silico analysis predicts Ala797Asp is probably damaging to protein structure/function. Variants in nearby residues (Glu788Asp, Glu788Lys, Arg791Trp, Gly800Glu, Gly800Trp) have been reported in HGMD in association with LQTS, supporting the functional importance of this region of the protein. Futhermore, Ala797Asp is not observed among the 6500 individuals of European and African-American ancestry in the NHLBI Exome Sequencing Project, indicating that it is not a common benign variant in these populations. Nonetheless, approximately 4% of Caucasian control individuals harbor a rare variant in one of the 3 major LQTS genes. It is not entirely possible to tell from location if a variant in KCNH2 may cause disease, but there are some clues available. When Kapa et al. (2009) compared 388 “clinically definite” LQTS probands to 1300 healthy controls, they found that some controls do have variants in the C-terminal region of the KCNH2 protein, where Ala797Asp falls. By contrast, no control had a variant in the KCNH2 pore region, transmembrane region, or linker region—indicating that changes in these other regions may have a high probability of causing LQTS. Residue 797, however, falls in the specialized cyclic nucleotide binding domain (cNBD) of KCNH2 (a.a. 742-842), where no control variants were observed by the authors, who conclude that this cNBD area of the C-terminus is more likely to be pathogenic. If this variant is pathogenic, there is some evidence that it may be less so than changes in other regions of KCNH2. The C-terminal region, relatively speaking, may be a region of lower risk for life-threatening events in LQTS. Shimizu et al. (2009) and Migdalovich et al. (2011) have analyzed the different levels of risk for variants located in different regions of the KCNH2 protein. For patients with missense mutations, Shimizu et al. found that the transmembrane pore (S5-loop-S6) and N-terminus regions presented a significantly greater risk than the C-terminus region where our patient’s variant is located (hazard ratio [HR]: 2.87 and 1.86, respectively). Migdalovich et al. similarly found that men (but not women) with pore-loop mutations displayed a 2-fold higher risk of a first aborted cardiac arrest or sudden cardiac death as compared with those with non–pore-loop mutations (HR: 2.18). A pathogenic role for this variant would be supported by evidence that it is de novo in an affected individual, or that it co-segregates with LQTS within an affected family.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.