Submissions for variant NM_000238.4(KCNH2):c.442C>T (p.Arg148Trp)

gnomAD frequency: 0.00062  dbSNP: rs139544114

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000148528	SCV000050827	benign	Long QT syndrome	2013-06-24	criteria provided, single submitter	research
GeneDx	RCV000058234	SCV000234061	benign	not provided	2020-03-10	criteria provided, single submitter	clinical testing	The R148W variant has been observed in 0.1% global alleles, including 1.6% of alleles from individuals of Ashkenazi Jewish ancestry and three individuals reported to be homozygous, in large population cohorts (Lek et al., 2016).; This variant is associated with the following publications: (PMID: 17088455, 19322600, 19841300, 20400443, 21410720, 22949429, 24055113, 23465283, 24334129, 25637381, 26159999, 27153395, 27875062, 27650965, 28988457, 31043699, 32048431)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000148528	SCV000253124	likely benign	Long QT syndrome	2024-01-22	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000223902	SCV000539436	uncertain significance	not specified	2016-04-25	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: Multiple reports as VUS/polymorphism, ExAC: 0.1% (99/66588) European chromosomes
Eurofins Ntd Llc (ga)	RCV000223902	SCV000700686	likely benign	not specified	2016-10-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000618143	SCV000736190	benign	Cardiovascular phenotype	2017-10-20	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, 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.
Color Diagnostics, LLC DBA Color Health	RCV001841760	SCV000903679	benign	Cardiac arrhythmia	2018-03-16	criteria provided, single submitter	clinical testing
Mendelics	RCV000988004	SCV001137550	benign	Long QT syndrome 2	2019-05-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000988004	SCV001326853	likely benign	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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV001256843	SCV001433328	uncertain significance	Conduction disorder of the heart	2019-06-27	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000058234	SCV002821862	likely benign	not provided	2024-08-01	criteria provided, single submitter	clinical testing	KCNH2: BS1
Dept of Medical Biology, Uskudar University	RCV000148528	SCV004021949	uncertain significance	Long QT syndrome	2024-01-08	criteria provided, single submitter	research	Criteria: PP2, PP3, BS1
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000058234	SCV000089754	not provided	not provided		no assertion provided	literature only	This variant has been reported in the following publications (PMID:19322600;PMID:19841300;PMID:21410720).
CSER _CC_NCGL, University of Washington	RCV000148528	SCV000190240	uncertain significance	Long QT syndrome	2014-06-01	no assertion criteria provided	research
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000223902	SCV000280131	uncertain significance	not specified	2013-01-18	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.Arg148Trp Given the data reviewed below we also consider it a variant of uncertain significance. Millat et al (2009) observed the variant in a 4mo male SIDS case. Kapa et al (2009) report the variant as a polymorphism. They do not provide the frequency of the variant in controls but note that they considered something a polymorphism if it was seen more than once in the 1369 controls they studied. This same group reported the variant in a case of autopsy-negative sudden cardiac death but noted it was a "less common polymorphism" without functional data supporting pathogenicity. Novotny et al (2011) sequenced several long QT genes in individuals with coronary artery disease and ventricular fibrillation and observed this variant in one individual. Crotti et al (2012) reported the variant in one individual with long QT syndrome. No ancestry or segregation data were provided. The variant is in the N-terminal region of the protein. In total the variant has been seen in 25 of 7164 individuals in publicly available general population samples. The variant is listed in dbSNP (rs139544114), pointing to the NHLBI ESP data and also noting that ~9/661 individuals in the ClinSeq population from NIH (a general population cohort) were heterozygotes. The variant was reported online in 16 of 4300 Caucasian individuals and 0 of 2203 African-American individuals in the NHLBI Exome Sequencing Project dataset (as of January 18th, 2012). The phenotype of those individuals is not publicly available, however the cohorts that were merged to create this dataset were all either general population samples or samples recruited for common cardiovascular disease such as hypertension.
Clinical Genetics, Academic Medical Center	RCV000058234	SCV001923136	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000058234	SCV001929832	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000058234	SCV001957022	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000058234	SCV001965043	likely benign	not provided		no assertion criteria provided	clinical testing