ClinVar Miner

Submissions for variant NM_000238.4(KCNH2):c.1282T>C (p.Ser428Pro)

dbSNP: rs794728368
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000181787 SCV000234090 likely pathogenic not provided 2014-03-26 criteria provided, single submitter clinical testing p.Ser428Pro (TCG>CCG): c.1282 T>C in exon 6 of the KCNH2 (HERG) gene (NM_000238.2). While the S428P mutation in the KCNH2 gene has not been published to our knowledge, this mutation has been observed in one other unrelated individual tested for LQTS at GeneDx. Additionally, mutations affecting this same residue (S428L) and nearby residues (Y427H, Y427S, Y427C, A429P) have been reported in association with LQTS (Moss A et al, 2002; Napolitano C et al., 2005), supporting the functional importance of this residue and this region of the protein. In silico analysis predicts S428P is damaging to the protein structure/function. Furthermore, S428P was not observed in approximately 6500 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, S428P in the KCNH2 gene is interpreted as a likely disease-causing mutation. The variant is found in LQT, ARRHYTHMIA panel(s).
All of Us Research Program, National Institutes of Health RCV003996707 SCV004844015 uncertain significance Long QT syndrome 2023-05-16 criteria provided, single submitter clinical testing This missense variant replaces serine with proline at codon 428 of the KCNH2 protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals suspected to be affected with long QT syndrome (PMID: 23631430; ClinVar SCV000234090.8). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The 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.

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