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

Total submissions: 10

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.