ClinVar Miner

Submissions for variant NM_000238.4(KCNH2):c.3470C>T (p.Pro1157Leu)

gnomAD frequency: 0.00003  dbSNP: rs143167166
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000181918 SCV000234221 uncertain significance not provided 2021-06-22 criteria provided, single submitter clinical testing Reported in one case of sudden infant death (Tester et al. 2005); Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Immunoblot analysis of HEK293 cells transfected with this variant demonstrated protein trafficking to the cell membrane similar to wildtype (Anderson et al., 2014); Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 67499; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 15913580, 31043699, 23465283, 27535533, 25417810, 26582918)
Color Diagnostics, LLC DBA Color Health RCV001841757 SCV001342496 uncertain significance Cardiac arrhythmia 2023-05-01 criteria provided, single submitter clinical testing This missense variant replaces proline with leucine at codon 1157 of the KCNH2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). An in-vitro functional study using transfected HEK293 cells has shown that this variant may not impact trafficking (PMID: 25417810). This variant has been reported in an individual affected with sudden unexplained death (PMID: 15913580). This variant has been identified in 4/205408 chromosomes 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.
Labcorp Genetics (formerly Invitae), Labcorp RCV001321433 SCV001512261 uncertain significance Long QT syndrome 2022-10-17 criteria provided, single submitter clinical testing This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1157 of the KCNH2 protein (p.Pro1157Leu). This variant is present in population databases (rs143167166, gnomAD 0.009%). This missense change has been observed in individual(s) with sudden infant death syndrome (PMID: 15913580). ClinVar contains an entry for this variant (Variation ID: 67499). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change does not substantially affect KCNH2 function (PMID: 25417810). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
All of Us Research Program, National Institutes of Health RCV001321433 SCV004835829 uncertain significance Long QT syndrome 2023-12-13 criteria provided, single submitter clinical testing This missense variant replaces proline with leucine at codon 1157 of the KCNH2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). An in-vitro functional study using transfected HEK293 cells has shown that this variant may not impact trafficking (PMID: 25417810). This variant has been reported in an individual affected with sudden unexplained death (PMID: 15913580). This variant has been identified in 4/205408 chromosomes 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.
Ambry Genetics RCV004019020 SCV004888827 uncertain significance Cardiovascular phenotype 2022-05-03 criteria provided, single submitter clinical testing The c.3470C>T (p.P1157L) alteration is located in exon 15 (coding exon 15) of the KCNH2 gene. This alteration results from a C to T substitution at nucleotide position 3470, causing the proline (P) at amino acid position 1157 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust RCV000058228 SCV000089748 not provided SUDDEN INFANT DEATH SYNDROME no assertion provided literature only This variant has been reported as associated with Sudden infant death syndrome in the following publications (PMID:15913580). 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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