ClinVar Miner

Submissions for variant NM_172057.2(KCNH2):c.2345C>G (p.Pro782Arg) (rs531460655)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000223795 SCV000280130 uncertain significance not specified 2014-07-03 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.Pro1122Arg Based on the evidence reviewed below, we classify it as a variant of unknown significance (VUS), concluding that there is not yet sufficient evidence for its pathogenicity. This is a novel variant, not published in the literature. No nearby missense variants in KCNH2 have been associated with LQTS (according to the inherited arrhythmias database updated by Dr. Silvia Priori’s Cardiovascular Genetics Program at NYU School of Medicine). We are not able to check HGMD for such variants. This is a non-conservative amino acid change, in which a nonpolar proline is replaced by a positively-charged arginine. The proline at this location is not well conserved across 31 vertebrate species. In silico analysis with PolyPhen-2 (http://genetics.bwh.harvard.edu/pph2/) predicts the variant to be “possibly damaging” with a score of 0.929. It is not entirely possible to tell from location if a variant in KCNH2 may cause disease, but there are some clues. 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 residue 1122 falls. (Controls did include 180 Hispanic individuals.) 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. 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) No variation at this residue is present in ~6500 individuals from the NHLBI Exome Sequencing Project dataset (http://evs.gs.washington.edu/EVS/), which currently includes variant calls on ~4300 Caucasian and ~2200 African American individuals. It is also not present in the 1000 Genomes database.

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