ClinVar Genomic variation as it relates to human health

The KCNQ1 c.830C>T variant is predicted to result in the amino acid substitution p.Ser277Leu. This variant was reported to be causative for long QT syndrome and/or sudden cardiac death, and was found to segregate in multiple families (Liu et al. 2002. PubMed ID: 12442276; Yagi et al. 2018. PubMed ID: 29439887; Table S1, Schwartz et al. 2021. PubMed ID: 34505893; Akgun-Dogan et al. 2021. PubMed ID: 34860437). Functional studies showed that this variant results in reduced surface expression and loss of potassium channel function (Chen et al. 2011. PubMed ID: 21895724). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic.

The p.S277L pathogenic mutation (also known as c.830C>T), located in coding exon 6 of the KCNQ1 gene, results from a C to T substitution at nucleotide position 830. The serine at codon 277 is replaced by leucine, an amino acid with dissimilar properties, and is located in the S5 transmembrane domain. This alteration has been reported in individuals with long QT syndrome (LQTS) and has been shown to segregate with disease in several families (Liu W et al. Hum. Mutat., 2002 Dec;20:475-6; Aidery P et al. Biochim. Biophys. Acta, 2011 Apr;1812:488-94; Chen J et al. Pacing Clin Electrophysiol, 2011 Dec;34:1652-64; Yagi N et al. J Cardiol. 2018 07;72(1):56-65). This alteration has also been detected in LQTS cohorts, but clinical details were limited (Kapplinger JD et al. Heart Rhythm, 2009 Sep;6:1297-303; Hayashi K et al. Journ Am Coll Cardiol EP, 2016 Feb;2:279–87). Additionally, functional studies have demonstrated that this alteration results in the complete loss of cardiac voltage-gated potassium channel function (Aidery P et al. Biochim. Biophys. Acta, 2011 Apr;1812:488-94; Chen J et al. Pacing Clin Electrophysiol, 2011 Dec;34:1652-64). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

PS3, PM1, PM2, PM5

The KCNQ1 c.830C>T variant is classified as Pathogenic (PS3, PS4, PP1_Strong, PM2) The KCNQ1 c.830C>T variant is a single nucleotide change in exon 6/16 of the KCNQ1 gene, which is predicted to change the amino acid serine at position 277 in the protein, to leucine. The variant has been reported in at least 17 probands with a clinical presentation of Long QT Syndrome (PMID#19716085, 12442276, 34860437, 29439887, 21241800, 21895724, 12442296)(PS4) and is rare in population databases (gnomAD allele frequency = 0.00065%; 1 het and 0 hom) (PM2). This variant is reported to co-segregate with disease in 10 individuals in 14 families (PMID#29439887, 21241800, 21895724, 12442276) (PP1_strong). Well-established functional studies show a deleterious effect of this variant on the resultant protein (PMID#21241800, 21895724) (PS3) and computational predictions support a deleterious effect on the gene or gene product. The variant has been reported in dbSNP (rs199472730), is reported as disease causing in the HGMD database (CM023402) and is reported as pathogenic by other diagnostic laboratories (ClinVar Variation ID: 53116).

This missense variant replaces serine with leucine at codon 277 in transmembrane domain S5 of the KCNQ1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that in transfected cells this variant does not produce functional potassium channels, suppresses wild-type currents in dominant-negative manner, and causes trafficking defect that results in reduced surface expression (PMID: 21241800, 21895724). This variant has been reported in over 15 unrelated individuals affected with long QT syndrome (PMID: 12442276, 21241800, 21895724, 21241800, 27920829, 32893267). Multiple affected relative carriers have been reported in some of these families (PMID: 12442276, 15234419, 26063740, 29439887) and segregation with disease has been observed in a few families with long QT syndrome although segregation details are not available (ClinVar SCV000280165.1, SCV000234426.12). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.

This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 277 of the KCNQ1 protein (p.Ser277Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with long QT syndrome (PMID: 12442276, 19716085, 21241800, 21895724). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 53116). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects KCNQ1 function (PMID: 21241800, 21895724). For these reasons, this variant has been classified as Pathogenic.

The p.Ser277Leu variant in KCNQ1 has been reported in 14 heterozygous individuals with long QT syndrome (LQTS) and segregated with disease in at least 8 affected relatives from multiple families (Liu 2002, Chen2011, Aidery 2011, Yoshinaga 2014, Yagi 2018). This variant has also been reported in ClinVar (Variation ID: 53116), but was absent from large population databases. Computational prediction tools and conservation analysis suggest that the p.Ser277Leu variant may impact the protein. In vitro functional studies provide evidence that the p.Ser277Leu variant may have a dominant-negative effect on protein's expression and function (Aidery 2011, Chen 2011). Other missense variants at this codon (p.Ser277Pro and p.Ser277Trp) have also been associated with LQTS (Kapplinger 2009, Napolitano 2005), suggesting that a change at this position might not be tolerated. In summary, this variant meets criteria to be classified as pathogenic for long QT syndrome in an autosomal dominant manner based upon clinical data, segregation studies and functional evidence. ACMG/AMP criteria applied: PP1_Strong, PM2, PS4_Moderate, PP3, PS3_Supporting.

Reported in association with LQTS in patients referred for genetic testing at GeneDx and in the published literature (PMID: 19716085, 12442276, 15234419, 17470695, 26823142, 34319147, 29439887); 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; Published functional studies demonstrate a damaging effect as this variant suppresses the function of the wild type potassium channel indicating this pathogenic variant has a dominant-negative effect (PMID: 21241800, 21895724); This variant is associated with the following publications: (PMID: 21895724, 21241800, 26344792, 12442276, 26823142, 27041096, 15840476, 17470695, 15234419, 30535908, 34860437, 34319147, 29439887, 19716085, 34505893, 34135346)

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.Ser277Leu Given the strong case data, other disease-associated variants at the same codon, and absence in controls, we consider this variant likely disease causing. The variant has been seen in at least 7 unrelated cases of long QT. There is weak segregation data. Liu et al (2002) identified the variant in 1 of 42 unrelated Chinese long QT patients. It sounds like the variant was also presented in some of the other affected family members but details of segregation are not provided. Presumably that overlaps with a later paper by the same group (Liu et al 2006). Another Chinese group reported the variant in 1 of 10 long QT patients (Li et al 2004). Unfortunately the article is in Chinese. The variant was reported in 2 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 cohort 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). Chen et al (2011) identified the variant in a 26-year-old Hispanic woman with long QT who died suddenly. Shimizu et al (2004) reported the variant in 2 of 37 unrelated long QT patients from their Japanese registry. Three patients with this variant were included in a paper by Moss et al (2007), however given recruitment methods these likely overlap with other reports. There is some segregation data in a family with LQTS through our center, involving three individuals who are either obligate carriers or have a diagnosis of long QT syndrome and carry the variant. Other variants have been reported in association with disease at this codon (p.Ser277Pro, p.Ser277Trp) and nearby codons (p.Ph275Ser, p.Tyr278His). Per the GeneDx report, " Functional studies report S277L affects potassium ion channel function and suppresses the function of the wild type, indicating this mutation has a dominant-negative effect (Aidery P et al., 2011)." Chen et al (2011) also observed a dominant negative reduction in KCNQ1 and IKs current density. They observed a trafficking defect that results in reduced surface expression. The variant is in the S5 transmembrane domain. In total the variant has not been seen in~65,400 published controls and individuals from publicly available population datasets. There is also no variation at this codon listed in dbSNP or 1000 genomes (as of December 17th, 2014). The variant was not observed in the following published control samples: 100 (Liu et al 2002), 1300 (Kapplinger et al 2009). There is no nonsynonymous variation at codon 277 listed 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 December 17th, 2014). Of note considering the Asian cases, this includes 4,360 east Asian individuals.

This variant has been reported as associated with Long QT syndrome in the following publications (PMID:12442276;PMID:15192825;PMID:15840476;PMID:16831322;PMID:19716085;PMID:21241800;PMID:21895724;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.