Submissions for variant NM_000238.4(KCNH2):c.1039C>T (p.Pro347Ser)

gnomAD frequency: 0.00061  dbSNP: rs138776684

Total submissions: 19

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	likely benign	not provided	2022-10-05	criteria provided, single submitter	clinical testing	See Variant Classification Assertion Criteria.
Invitae	RCV000148527	SCV000283956	benign	Long QT syndrome	2024-01-31	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham 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	2018-06-07	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
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 Diagnostics, LLC DBA Color Health	RCV001841694	SCV000903203	likely benign	Cardiac arrhythmia	2018-03-16	criteria provided, single submitter	clinical testing
Mendelics	RCV000678963	SCV001137547	benign	Long QT syndrome 2	2019-05-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000678963	SCV001324604	uncertain significance	Long QT syndrome 2	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000678963	SCV001428618	uncertain significance	Long QT syndrome 2	2016-11-21	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000181777	SCV002819810	likely benign	not specified	2022-12-25	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000057870	SCV004010740	likely benign	not provided	2024-01-01	criteria provided, single submitter	clinical testing	KCNH2: BP4, BS1
PreventionGenetics, part of Exact Sciences	RCV003944978	SCV004758146	likely benign	KCNH2-related condition	2022-08-17	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
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	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.
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000057870	SCV002034249	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000057870	SCV002034415	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000057870	SCV002037511	likely benign	not provided		no assertion criteria provided	clinical testing