Submissions for variant NM_000238.4(KCNH2):c.3278C>T (p.Pro1093Leu)

gnomAD frequency: 0.00007  dbSNP: rs199473545

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000223703	SCV000539439	uncertain significance	not specified	2016-06-16	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: Reported in 2 probands, 1 functional study suggests benign
Color Diagnostics, LLC DBA Color Health	RCV001841749	SCV000913648	uncertain significance	Cardiac arrhythmia	2018-09-04	criteria provided, single submitter	clinical testing	Variant of Uncertain Significance due to insufficient evidence: This missense variant is located in the cytoplasmic domain of the KCNH2 protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact the RNA splicing. To our knowledge, functional assays have not been performed for this variant. This variant has been reported in an individual with arrhythmia (PMID: 28567303), in an individual with a family history of sudden cardiac death (PMID: 21499742) and in an individual affected with typical Andersen-Tawil syndrome, who also carried a variant in the KCNJ2 gene (PMID: 22589293). This variant has also been identified in 9/238484 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively.
Institute of Human Genetics, University of Leipzig Medical Center	RCV001253513	SCV001429255	uncertain significance	Long QT syndrome 2	2019-11-26	criteria provided, single submitter	clinical testing
Invitae	RCV001309472	SCV001498971	uncertain significance	Long QT syndrome	2024-01-27	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 1093 of the KCNH2 protein (p.Pro1093Leu). This variant is present in population databases (rs199473545, gnomAD 0.006%). This missense change has been observed in individual(s) with clinical features of long QT syndrome (PMID: 19716085, 22949429, 29727688). ClinVar contains an entry for this variant (Variation ID: 67485). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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.
Fulgent Genetics, Fulgent Genetics	RCV002504966	SCV002815924	uncertain significance	Short QT syndrome type 1; Long QT syndrome 2	2021-07-08	criteria provided, single submitter	clinical testing
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000058214	SCV000089734	not provided	Congenital long QT syndrome		no assertion provided	literature only	This variant has been reported as associated with Long QT syndrome in the following publications (PMID:19716085;PMID:19841300). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000223703	SCV000280129	uncertain significance	not specified	2012-06-13	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.Pro1093Leu Based on the data reviewed below we consider it a variant of uncertain significance. There is also a possibility that it is a modifier and not the primary driver of disease. The variant has been seen in at least 1 case of long QT syndrome. The variant was reported in two individuals in the Familion compendium, which includes 2500 patients referred for clinical long QT genetic testing (Kapplinger et al 2009). Those cases likely overlap with the data in Kapa et al (2009) and Giudicessi et al (2012) since these are all from Ackerman's group. Of note in considering the other case reported by Kapplinger et al (2009) is the lack of phenotypic data on this cohort, the low yield of 36% (vs. 70% in cohorts with firm diagnoses of long QT), and the lack of clarity regarding which variants were seen in isolated and which were seen with another variant (9% of the cohort had multiple variants). In a presentation online by Kimura et al they note that they observed the variant in a patient with Anderson-Tawil syndrome, who also carried p.Arg82Trp in KCNJ2 (Anderson-Tawil is caused by pathogenic variants in KCNJ2). In silico analysis with PolyPhen-2 predicts the variant to be benign and SIFT predicts it to be tolerated. The proline at codon 1093 is conserved across species, as are neighboring amino acids. No other variants have been reported in association with disease at this codon and nearby codons. However, nearby variants suspected to be benign have been reported (p.Ser1092Phe, p.Val1097Ile). The variant is in the c-terminal region of the protein. Kapa et al (2012) report that variants in this region have a 73% likelihood of being associated with long QT syndrome (vs. 100% in the transmembrane region). In total the variant has not been seen in ~ 7800 laboratory controls, published controls and individuals from publicly available population datasets. There is no variation at codon 1093 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6500 Caucasian and African American individuals (as of December 31st, 2013). The variant is listed in dbSNP but only in reference to the long QT associated data reviewed above (rs199473545). The variant was not observed in the following laboratory and published control samples: 1300 presumed health individuals of varying ethnicities studied by Kapplinger et al (2009).