11-2583457-A-G
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000218.3(KCNQ1):c.944A>G(p.Tyr315Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,218 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y315F) has been classified as Pathogenic.
Frequency
Consequence
NM_000218.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| KCNQ1 | ENST00000155840.12 | c.944A>G | p.Tyr315Cys | missense_variant | Exon 7 of 16 | 1 | NM_000218.3 | ENSP00000155840.2 | ||
| KCNQ1 | ENST00000335475.6 | c.563A>G | p.Tyr188Cys | missense_variant | Exon 7 of 16 | 1 | ENSP00000334497.5 | |||
| KCNQ1 | ENST00000496887.7 | c.683A>G | p.Tyr228Cys | missense_variant | Exon 8 of 16 | 5 | ENSP00000434560.2 | |||
| KCNQ1 | ENST00000646564.2 | c.500A>G | p.Tyr167Cys | missense_variant | Exon 3 of 11 | ENSP00000495806.2 |
Frequencies
GnomAD3 genomes
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461218Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 726932
GnomAD4 genome
ClinVar
Submissions by phenotype
not provided Pathogenic:4
Published functional studies demonstrate a damaging effect as this variant results in reduced potassium channel current in vitro (Bianchi et al., 2000); 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; This variant is associated with the following publications: (PMID: 15466642, 24269949, 19490272, 14678125, 9693036, 9927399, 17470695, 15840476, 19261104, 23575362, 23130128, 12877697, 12702160, 24606995, 18774102, 23098067, 19716085, 24217263, 28749187, 27920829, 28438721, 10868744, 14760488, 20541041, 10220144, 31447099, 34135346, 11087258) -
KCNQ1: PM1, PM2, PM5, PS4:Moderate, PP3, PS3:Supporting -
PP3, PM1, PM2, PS3, PS4 -
p.Tyr315Cys (c.944A>G, p.Y315C) in the KCNQ1 gene The variant was re-reviewed March 2nd, 2016. There was both new case data and new allele frequency data, both of which further support pathogenicity and shift our classification from likely pathogenic to pathogenic. The variant has been seen in at least 13 unrelated cases of long QT syndrome (not including this patient). We seen this variant in one other family with long QT in our center. Splawski et al (1998) reported this variant in a patient with long QT syndrome, presumably from their American cohort (ancestry not noted). Priori et al (1999) reported the variant in a patient from their Italian cohort with long QT syndrome. Chen et al (2003) observed the variant in two siblings with long QT syndrome (cohort studied at Cleveland clinic, recruited from clinics in North America, South America, Europe; ancestry not provided). Choi et al (2004) reported the variant in an "LQT1 index case" (no other phenotypic data provided) who had a cousin with exertional syncope and a near-drowning event (cohort studied in Dr. Ackerman's lab at Mayo; ancestry not provided). This case likely overlaps with Nemec et al (2003) and Tester et al (2005), also from Dr. Ackerman's group. The variant was observed in 4 patients included in the Familion compendium publication with no phenotype or ancestry data (Kapplinger et al 2009). This publication reports on variants observed in patients referred for long QT syndrome genetic testing using the Familion test at PGxHealth (now Transgenomics). Napolitano et al (2000) reported the variant in a woman with QT-prolongation and arrest in the setting of a QT-prolonging medication (cisapride) (ancestry not noted but patient likely from Italy). Patients with this variant are included in two papers on genotype-phenotype correlations (Zareba et al 2003, Moss et al 2007). The subjects were drawn from the various long QT registries and many of the authors overlap with the other publications reviewed here, so at least some of the cases are likely redundant with those summarized above. Stattin et al (2012) studied 200 unrelated index cases of LQTS referred for care in Sweden between 3/2006 and 10/2009. KCNQ1, KCNH2, KCNE1, KCNE2, and SCN5A were analyzed. The variant of interest was found in a single proband; no segregation data is reported. Hedley et al (2013) studied 44 South African congenital LQTS patients, screening them for variants in the coding regions of KCNQ1, KCNH2, KCNE1, KCNE2, and SCN5A. The variant of interest was found in one patient (no segregation data reported). Christiansen et al (2014) assessed 70 unrelated Danish LQTS probands by variant screening of KCNQ1, KCNH2, KCNE1, KCNE2, and SCN5A. The variant of interest was found in a single proband; no segregation data is reported. In silico analysis with PolyPhen-2 predicts the variant to be probably damaging. Grantham score is 5.29. The tyrosine at codon 315 is completely conserved across species, as are neighboring amino acids. Other variants have been reported in association with disease at this codon (p.Tyr315Ser, p.Tyr315Phe) and nearby codons (p.Ile313Met, p.Gly314Asp, p.Gly314Ala, p.Gly314Ser, p.Gly314Cys, p.Gly314Arg, p.Gly314Val, p.GLy316Glu, p.GLy316Arg). Functional studies have shown a decrease in potassium current (Bianchi et al 2000). The variant is in the pore region of the channel. Variants in this region are much more likely to be pathogenic than benign. There is also some evidence that they confer a higher risk of events (Moss et al 2007), though other studies have not found such a difference (Zareba et al 2003). Barsheshet et al (2012) found that carriers of missense variants in the cytoplasmic loops had the highest risk of events as well as the greatest response to beta-blockade. The patient's variant is not in the cytoplasmic loop. Moss et al (2007) reported a higher risk with dominant negative variants and classify this variant as dominant negative. In total the variant has no -
Long QT syndrome Pathogenic:3
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This missense variant replaces tyrosine with cysteine at codon 315 of the KCNQ1 protein. This variant is found within the highly conserved pore-forming domain (a.a. 300-320). Rare non-truncating variants in this region have been shown to be significantly overrepresented in individuals with long QT syndrome (PMID: 32893267). Functional studies have shown that the mutant protein exhibits a dominant negative effect when it forms a complex with a wild type protein, resulting in a dysfunctional potassium channel (PMID: 11087258, 21451124). This variant has been reported in over 15 unrelated individuals affected with long QT syndrome (PMID: 28438721, 32893267, 36102233). Additionally, this variant has been reported to be associated with a prolonged QTc interval and with having a diagnosis of long QT syndrome (OR 228.9; 95% CI = 58.24-899.6) in the Icelandic population (PMID: 37449562, ClinVar SCV004022220.1). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Different missense variants occurring at the same codon, p.Tyr315Ser and p.Tyr315His, are known to cause disease (Clinvar variation ID: 53139, 449302), indicating that tyrosine at this position is important for the protein function. Based on the available evidence, this variant is classified as Likely Pathogenic. -
This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 315 of the KCNQ1 protein (p.Tyr315Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with long QT syndrome (PMID: 9693036, 12702160, 18774102, 21451124, 24217263, 24606995). ClinVar contains an entry for this variant (Variation ID: 53140). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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: 11087258, 21451124). For these reasons, this variant has been classified as Pathogenic. -
Long QT syndrome 1 Pathogenic:2
The c.944A>G (p.Tyr315Cys) variant in the KCNQ1 gene has been observed in multiple individuals with long QT syndrome (PMID: 9693036, 10868744, 12702160, 15840476, 14760488, 15466642). In addition, experimental studies have shown that this missense change leads to altered KCNQ1 protein function (PMID: 11087258). The c.944A>G (p.Tyr315Cys) variant in the KCNQ1 gene is classified as likely pathogenic. -
The variant NM_000218.3:c.944A>G (chr11:2583457) in KCNQ1 was detected in 17 heterozygotes out of 58K WGS Icelanders (MAF= 0,015%). Following imputation in a set of 166K Icelanders (48 imputed heterozygotes) we observed an association with an elongation of the qt interval on ECG using measurements from 80068 individuals (Effect (SD)= 2.21, P= 5.38e-26) and heart failure using 20765 cases and 367806 controls (OR= 3.17, P= 1.31e-02). This variant has been reported in ClinVar previously as pathogenic/likely pathogenic. Based on ACMG criteria (PS4, PM1, PP3, PP5) this variant classifies as likely pathogenic. -
Cardiovascular phenotype Pathogenic:1
The p.Y315C pathogenic mutation (also known as c.944A>G), located in coding exon 7 of the KCNQ1 gene, results from an A to G substitution at nucleotide position 944. The tyrosine at codon 315 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration impacts the highly conserved ion selectivity filter (TIGYGD) located between transmembrane helices S5 and S6. This alteration has been detected in multiple unrelated individuals reported to have confirmed or suspected long QT syndrome, with variable expressivity in some cases (LQTS) (Splawski I et al. Genomics. 1998;51(1):86-97; Chen S et al. Clin Genet. 2003;63(4):273-82; Moss AJ et al. Circulation. 2007; Kapplinger JD et al. Heart Rhythm. 2009;6(9):1297-303; 115(19):2481-9; Itoh H et al. Heart Rhythm. 2010;7(10):1411-8; Bartos DC et al. Heart Rhythm. 2014;11(3):459-68). One study reported this alteration to result in a dominant negative effect on wild-type IKs current when expressed with wild-type channel in vitro (Bianchi L et al. Am J Physiol Heart Circ Physiol. 2000;279(6):H3003-11). Internal structural analysis indicates that this variant disrupts the ion channel pore and is expected to eliminate the K+ selectivity of the K+ channel (Tao X et al. Science. 2009;326(5960):1668-74; Whorton MR and MacKinnon R. Cell. 2011;147(1):199-208; Ambry internal data). In addition, another alteration affecting this codon (p.Y315S, c.944A>C) has also been reported in association with LQTS (Jongbloed RJ et al. Hum Mutat. 1999;13(4):301-10). 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. -
Congenital long QT syndrome Other:1
This variant has been reported as associated with Long QT syndrome in the following publications (PMID:9693036;PMID:10868744;PMID:12702160;PMID:12877697;PMID:14678125;PMID:14760488;PMID:15466642;PMID:15840476;PMID:19716085;PMID:9927399;PMID:17470695). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at