ClinVar Miner

Submissions for variant NM_172056.2(KCNH2):c.1882G>A (p.Gly628Ser) (rs121912507)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 6
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000223848 SCV000490550 pathogenic not provided 2016-02-25 criteria provided, single submitter clinical testing The G628S pathogenic variant in the KCNH2 gene has been reported multiple times in association with LQTS, and was not seen in >1,369 healthy control individuals (Curran et al., 1995; Splawski et al., 2000; Shim et al., 2005; Anderson et al., 2006; Kapa et al., 2009; Giudicessi et al., 2012). Of note, G628S was identified as a de novo variant in a neonate presenting with fetal bradycardia, torsades de pointes, 2:1 atrioventricular block, a QTc of 544 ms, and heart failure; family history was negative and both parents had a normal QTc interval (Lupoglazoff et al., 2004). Furthermore, the G628S variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The G628S variant results in a non-conservative amino acid substitution of a non-polar Glycine residue with a polar Serine residue, at a position that is highly conserved and important for potassium ion selectivity (Curran et al., 1995). The G628S variant is located in the pore-forming domain of the protein and alters the selectivity filter motif (Curran et al., 1995). Multiple functional studies demonstrated that G628S results in a loss of potassium channel function (Anderson et al., 2006; Brunner et al., 2008; Ren et al., 2010). In summary, G628S in the KCNH2 gene is interpreted as a pathogenic variant.
Center for Human Genetics and Laboratory Diagnostics, Dr. Klein, Dr. Rost and Colleagues RCV000015508 SCV000805159 pathogenic Long QT syndrome 2 2018-03-22 criteria provided, single submitter clinical testing
Invitae RCV000822422 SCV000963223 pathogenic Long QT syndrome 2018-08-29 criteria provided, single submitter clinical testing This sequence change replaces glycine with serine at codon 628 of the KCNH2 protein (p.Gly628Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals affected with long QT syndrome including affected individuals where the variant was observed de novo (PMID: 7889573, 14998624, 22949429, 17088455, 16922724). ClinVar contains an entry for this variant (Variation ID: 14427). Experimental studies have shown that this missense change results in failure to form functional ion channels (PMID: 9694858, 23303164, 8700910). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000015508 SCV000035773 pathogenic Long QT syndrome 2 1995-03-10 no assertion criteria provided literature only
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058029 SCV000089549 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:7889573;PMID:10973849;PMID:11854117;PMID:14998624;PMID:15840476;PMID:16379539;PMID:16432067;PMID:16922724;PMID:18441445;PMID:18464931;PMID:19716085;PMID:19841300;PMID:20833965;PMID:21806934;PMID:9694858;PMID:22876326). 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 RCV000223848 SCV000280122 likely pathogenic not provided 2013-11-15 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.Gly628Ser Based on the data reviewed below we consider this variant likely disease-causing. The variant has been seen in at least 6 unrelated cases of Long QT. There is no segregation data available. Curran et al (1995) was the first to report this variant in a proband with Long QT suggesting the connection between LongQt and KCNH2 (then known as the HERG gene). It was a de novo mutation. No clinical data or segregation data was given. Splawski et al. (2000) reported this variant in two families with LQT from a cohort of 262 individuals with LQTS. The authors tested for mutations in all known arrhythmia genes. No specific phenotype data was given for the patients. Lupoglazoff et al (2004) reported this variant in a neonate with fetal bradycardia and heart failure. This was a de novo mutation. No segregation data was given. Shim et al. 2005 reported this variant in a neonate with congenital LQT and a double heterozygote for a novel SCN5A varaint-V1950L. The patient was implanted with an ICD at 3 days. The patient's mother had LQT and the SCN5A mutation. The father did not carry the KCNH2 variant and it was thus de novo and thought to contribute to the patient's phenotype. Kapa et al., 2009 (Ackerman) reported this variant in one individual from their cohort of 388 LQT syndrome patients from 1997 to 2007. All had a clinical diagnostic score (Schwartz score) of >4 or a corrected QT interval (QTc) >480 ms. They did mutation analysis for KCNQ1, KCNH2, and SCN5A. Specific case data was not given for the patient with this variant. They reported an extremely high probability (EPV100%; 95% CI, 95 to 100) of pathogenicity for missense mutations localizing to the linker, transmembrane, and pore regions of KCNH2 but lower EPVs for missense mutations in the N terminus (63%; 95% CI, 17 to 84) or C terminus of KCNH2. This variant occurs in the pore-forming domain, which is highly conserved in all potassium channel subunits (Curran et al. 1995). This substitution in vitro caused potassium ion selectivity loss. This substitution has also been found to correctly insert into the cell surface membrane, but does not generate Kv11.1 channel function, presumable because of its location within the potassium selectivity filter (Anderson et al. 2006). This variant results in a non-conservative amino acid substitution of a non-polar Glycine with a polar Serine, at a position that is highly conserved. Other variants have been reported in association with disease at this codon (Gly628Ala, Gly628Val) and nearby codons (Phe627Leu, Phe627Ile, Asn629Asp, Asn629Ser, Asn629Thr, Asn629Ile, Asn629Lys). In total the variant has not been seen in ~8,100 laboratory controls, published controls and individuals from publicly available population datasets. There is no variation at codon 628 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6,500 Caucasian and African American individuals (as of 10/22/13). The variant was not observed in the following published control samples: Kapa did not report this variant in >1300 control individuals, Lupoglazoff did not report this variant in 100 control individuals, Splawski did not report this variant in 200 control individuals.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.