ClinVar Genomic variation as it relates to human health

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects KCNQ1 function (PMID: 23000022, 23092362). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt KCNQ1 protein function. ClinVar contains an entry for this variant (Variation ID: 53152). This missense change has been observed in individuals with long QT syndrome (PMID: 21118729, 22456477, 22949429, 23000022, 23092362, 23158531, 26669661). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 325 of the KCNQ1 protein (p.Gly325Arg).

The p.G325R pathogenic mutation (also known as c.973G>A), located in coding exon 7 of the KCNQ1 gene, results from a G to A substitution at nucleotide position 973. The glycine at codon 325 is replaced by arginine, an amino acid with dissimilar properties. This alteration (and another nucleotide change (c.973G>C) resulting in the same amino acid substitution) has been detected in multiple unrelated individuals reported to have long QT syndrome or prolonged QTc interval and has been reported to segregate with prolonged QTc intervals in families (Tanaka T et al. Circulation. 1997;95:565-7 (reported as G196R, GGG to AGG); Donger C et al. Circulation. 1997;96:2778-81; Splawski I et al. Circulation. 2000;102:1178-85; Lupoglazoff JM et al. J Am Coll Cardiol. 2004;43:826-30; Shimizu WJ et al. Am Coll Cardiol. 2004;44(1):117-25; Moss AJ et al. Circulation. 2007;115:2481-9; Kapa S et al. Circulation. 2009;120:1752-60; Crotti L et al. J Am Coll Cardiol. 2012;60(24):2515-24; Burgess DE et al. Biochemistry. 2012;51:9076-85). In addition, in vitro functional studies report this alteration to result in loss of function and dominant negative suppression of wild type channel current (Aidery P et al. Gene. 2012;511:26-33; Burgess DE et al. Biochemistry. 2012;51:9076-85). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in ClinVar as pathogenic (ClinVar Variant ID# 53152; ClinVar); Published functional studies demonstrate that G325R leads to non-functional channels and suppresses wild-type current (Aidery et al., 2012; Burgess et al., 2012); This variant is associated with the following publications: (PMID: 9024139, 19841300, 17470695, 22949429, 21118729, 19716085, 15234419, 9386136, 14998624, 23092362, 23098067, 10973849, 26669661, 28292826, 22456477, 17905336, 11668638, 22581653, 29447731, 23000022, 32383558, 30123799)

Criteria: PS1, PS4_Moderate, PM1_Strong, PM2, PP3

Variant summary: KCNQ1 c.973G>A (p.Gly325Arg) results in a non-conservative amino acid change located in the Ion transport domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251400 control chromosomes. c.973G>A has been reported in the literature in numerous individuals affected with LQTS, including a study that found the variant in 11 families in which the variant segregated with prolonged QTc in 15 individuals (Burgess_2012). Functional studies have reported the variant to lead to non-functional channel, resulting in a dominant negative suppression of wild-type current (Burgess_2012, Aidery_2012). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

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. KCNQ1 p.Gly325Arg This variant has been reported in at least 13 unrelated cases with Long QT syndrome. There weak segregation data on the variant. The variant is also referred to as p.Gly198Arg (NP_861463.1) and p.Gly196Arg (older numbering system?). Tanaka et al (1997) reported p.Gly196Arg in 1 out of 32 Japanese families with Long QT. Later papers reporting on p.Gly325Arg refer to Tanaka et al, suggesting this is the same variant. Several papers on KCNQ1 from 1996 and 1997 appear to use an older numbering system. The case reported by Tanaka et al (1997) may overlap with one later reported by Shimizu et al (2004) since both were recruited from throughout Japan. Donger et al (1997) reported the variant in 1 out of 20 French families with long QT. Within this family there were 5 carriers, 4 of which had a syncopal event before 10 years of age. Individual QTc was not reported, mean QTc for the family was 460 ms. Splawski et al (2000) later reported of 2 additional cases with the variant and long QT syndrome in a cohort recruited from North America and Europe (likely Italian since Priori is the only European author). Larsen et al (2001) report this variant in a genetic testing methods paper noting that the patients were Danish. Lupoglazoff et al (2004) genotyped neonates with ventricular rates less than 110 beats per minute, p.Gly325Arg was identified in 1 female with a QTc of 550ms and a fetal ventricular rate at 90 beats per minute. She was asymptomatic at age 2. This study population was recruited in France. Chung et al (2007) identified the variant in 1 out of 84 unrelated individuals with long QT from New Zealand and Australia. The patient was a 53 year old female of European descent with a QTc of 520ms. The variant was reported in 6 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 and use data from his lab and from the Familion cohort. Of note in considering the cases 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 with another variant (9% of the cohort had multiple variants). Aidery et al (2012) reported a patient with long QT and p.Gly325Arg; the patient was a female of German ancestry who was diagnosed at age 5 (QTc 480 ms). She had a history of VSD with spontaneous closure in early infancy and exhibited onychondystropy on hands and feet. She was asymptomatic at time of publication. Moss et al (2007) include this variant in their study on genotype-phenotype correlations, however the sample was drawn from the international registry, the Dutch registry, and the Japanese registry, so these cases may overlap with Shimizu et al (2004), Tanaka et al (1997), Kapa et al (2009) and Splawski et al (2000). Burgess et al (2012) report on a pool of patients with this variant. Many, and possibly all, of the cases likely overlap with prior reports given the overlap in authors. However, they provide individual and family level data in the supplement that is helpful. They report a total of 11 unrelated cases with segregation in multiple families; in at least 3 families the variant appears to segregate with disease in at least 2 individuals. This is a semi conservative amino acid change with a non polar, neutral Glycine replaced with a polar, positive Arginine. This variant is located in the S6 pore domain of the potassium channel. In silico (SIFT, PolyPhen 2) analysis predict the amino acid change to be deleterious and probably damaging to the resulting protein. Missense variants at the same codon (p.Gly325Glu, p.Gly325Trp, p.Gly325Arg) and nearby codons (p.Tyr315Cys, p.Tyr315Phe, p.Tyr315Ser, p.Tyr315Asn, p.Gly316Glu, p.Gly316Arg, p.Gly316Val, p.Asp317Gly, p.Asp317Asn, p.Asp317Tyr, p.Lys318Asn, p.Pro320Ala, p.Pro320Ser, p.Pro320His, p.Thr322Ala, p.Thr322Lys, p.Thr322Met) have been reported in association with long QT. There are no functional studies involving mouse models. However Adieray et al (2012) did demonstrate that p.Gly325Arg affected potassium channels were nonfunctional using a Xenopus oocyte model. Burgess et al (2012) studied the variant in vitro noting it led to non-functional channels and a dominant negative suppression of wildtype potassium channel current. In total the variant has not been seen in 8280 general population samples and published controls (including 1780 published controls). Donger et al (1997) reported that p.Gly325Arg was absent in 100 presumably healthy control individuals of unspecified ancestry. Tanaka et al (1997) did not identify the variant in 80 presumably healthy control individuals of Japanese ancestry. Splawski et al (2000) did not find the variant in 200 presumably healthy controls. Lupoglazoff et al (2004) did not observe p.Gly325Arg in 100 presumably healthy controls. Kapplinger et al (2009) reported that p.Gly325Arg was not observed in 1300 presumably healthy controls (47% Caucasian, 26% African American, 11% Hispanic, 10% Asian, and 6% unknown/other). Thus in total the variant was absent in 1880 presumably healthy controls. The variant is listed in dbSNP with the rs # 199472756; however there is no allele frequency data available. It is listed in 1000Genomes. There is no variation at codon 325 in the NHLBI ESP, which currently includes variant calls from ~6500 individuals (as of January 15th 2014).

This variant has been reported as associated with Long QT syndrome in the following publications (PMID:9024139;PMID:9386136;PMID:10973849;PMID:11668638;PMID:14998624;PMID:17905336;PMID:19716085;PMID:19841300;PMID:15234419;PMID:17470695). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.