ClinVar Miner

Submissions for variant NM_172056.2(KCNH2):c.1039C>T (p.Pro347Ser) (rs138776684)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000148527 SCV000055217 likely benign Long QT syndrome 2013-06-24 criteria provided, single submitter research
GeneDx RCV000057870 SCV000234080 uncertain significance not provided 2017-10-10 criteria provided, single submitter clinical testing The P347S variant in the KCNH2 gene has been reported previously in association with LQTS (Splawski et al, 2000; Jongbloed et al, 2002; Paulussen et al, 2004). Splawski et al. (2000) initially identified the P347S variant in one individual with LQTS, and this variant was absent in at least 400 control alleles. The P347S variant was subsequently identified in other individuals with LQTS, including one individual who had a normal baseline ECG but developed significant QT prolongation (640 msec) when administered medications known to prolong the QT interval (Jongbloed et al, 2002; Paulussen et al, 2004). However, another study found the P347S variant in 1/187 Caucasian control individuals (Ackerman et al, 2003), and P347S is observed at a frequency of 0.25% from individuals of South Asian ancestry (Lek et al., 2016). An in vivo assay measuring normal repolarization rescue in KCNH2-knockdown embryonic zebrafish demonstrated P347S rescued the phenotype but not as efficiently as wild type or known polymorphisms, suggesting P347S has a negative impact on proper repolarization (Jou et al., 2013). However, functional studies by Anderson et al. did not demonstrate any significant difference between P347S mutant and wild type KCNH2 channel function (Anderson et al, 2006). The P347S variant results in 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. The P347 residue is conserved in mammalian species. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.
Invitae RCV000148527 SCV000283956 benign Long QT syndrome 2017-12-29 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000181777 SCV000539428 likely benign not specified 2017-02-03 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This variant is present in HGMD associated to LQTS in 9 papers, with comments suggesting Benign-VUS. It is classified in ClinVar with 1 star as Benign by Stanford and Invitae, Likely benign by Biesecker lab, and VUS by GeneDx and CSER. It has a Max MAF in ExAC of 0.24% (38 South Asian alleles) and in gnomAD of 0.25% (78 South Asian, 21 Ashkenazi, and 160 european alleles).
Ambry Genetics RCV000619112 SCV000737808 likely benign Cardiovascular phenotype 2016-11-29 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Subpopulation frequency in support of benign classification,In silico models in agreement (benign)
Center for Human Genetics and Laboratory Diagnostics, Dr. Klein, Dr. Rost and Colleagues RCV000678963 SCV000805179 uncertain significance Long QT syndrome 2 2018-05-17 criteria provided, single submitter clinical testing
Color RCV000771204 SCV000903203 likely benign Arrhythmia 2018-03-16 criteria provided, single submitter clinical testing
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000057870 SCV000089390 not provided not provided no assertion provided literature only This variant has been reported in the following publications (PMID:10973849;PMID:12402336;PMID:14661677;PMID:14760488;PMID:16432067;PMID:19841300;PMID:21410720;PMID:22378279).
CSER_CC_NCGL; University of Washington Medical Center RCV000148527 SCV000190239 uncertain significance Long QT syndrome 2014-06-01 no assertion criteria provided research
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000181777 SCV000280115 benign not specified 2011-07-18 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.Pro347Ser Given an MAF of 0.2% in unselected individuals and the location in the protein, we consider this variant likely benign. The proline at codon 347 is not conserved across species. The variant is in the N terminus of the channel. Variants in this region are less likely to be pathogenic than variants in the channel or C terminus (Kapa et al 2009). The variant was reported online in 156 of 55,452 individuals in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of September 16, 2015). Specifically, the variant was observed in 38 of 7642 South Asian individuals (MAF 0.2%)and 111 of 30,876 European indivdiuals. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease.

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