ClinVar Miner

Submissions for variant NM_172056.2(KCNH2):c.125T>C (p.Ile42Thr) (rs199473488)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000181925 SCV000234228 pathogenic not provided 2013-03-15 criteria provided, single submitter clinical testing p.Ile42Thr (ATC>ACC): c.125 T>C in exon 2 of the KCNH2 (aka HERG) gene (NM_000238.2)While the Ile42Thr mutation in the KCNH2 gene has not been reported to our knowledge, a mutation affecting this same codon, Ile42Asn, has been reported in association with LQTS (Chung S et al., 2007). Additionally, mutations in nearby residues (Val41Ala, Val41Phe, Tyr43Asp, Tyr43Cys, Cys44Phe, Cys44Trp) have been reported in association with LQTS, further supporting the functional importance of this codon and this region of the protein. Ile42Thr results in a non-conservative amino acid substitution of a non-polar Isoleucine with a polar Threonine at a position that is conserved across species. In silico analysis predicts Ile42Thr is damaging to the protein structure/function. Furthermore, the Ile42Thr 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, Ile42Thr in the KCNH2 gene is interpreted as a likely disease-causing mutation. The variant is found in LQT panel(s).

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