ClinVar Miner

Submissions for variant NM_172056.2(KCNH2):c.2204C>T (p.Ser735Leu) (rs199472988)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000181842 SCV000234145 likely pathogenic not provided 2016-11-28 criteria provided, single submitter clinical testing The S735L variant has previously been reported in an newborn with bradycardia (Shim et al., 2005). It was also observed in the newborn's clinically unaffected father and was absent from the mother, who had a borderline QT interval (Shim et al., 2005). This variant has also been identified in one other unrelated individual referred for arrhythmia genetic testing at GeneDx. However, it has been classified in ClinVar as a variant of uncertain significance by another clinical laboratory (ClinVar SCV000254340.1; Landrum et al., 2016). Nevertheless, the S735L 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. The S735L variant 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. This substitution occurs at a position in the pore region of the potassium channel (Shim et al., 2005) that is conserved in mammals, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Furthermore, functional studies demonstrate that S735L may affect normal protein trafficking (Anderson et al., 2014).Therefore, this variant is likely pathogenic.
Invitae RCV000196406 SCV000254340 uncertain significance Long QT syndrome 2015-06-15 criteria provided, single submitter clinical testing This sequence change replaces serine with leucine at codon 735 of the KCNH2 protein (p.Ser735Leu). The serine residue is highly conserved and there is a large physicochemical difference between serine and leucine. This variant has been reported in the literature and is present in population databases (rs199472988, <0.01%). It was reported in an newborn with bradycardia, and was observed in the newborn's clinically unaffected father (PMID: 16379539). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C15"). Experimental studies have shown that this missense change may affect normal protein trafficking (PMID: 25417810), but the clinical significance of the this observation is uncertain. In summary, this is a rare missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance.
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058094 SCV000089614 not provided Congenital long QT syndrome no assertion provided literature only This variant has been reported as associated with Long QT syndrome in the following publications (PMID:16379539). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.

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