Description
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 not been seen in ~65,000 published controls and individuals from publicly available population datasets. The variant was not observed in the following laboratory and published control samples: Splawski et al (1998) did not observe the variant in 200 controls (ancestry not reported), Kapplinger et al (2009) did not observe the variant in 1300 control individuals of varying ancestries. The variant is not 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 3/1/16). However, another variation at codon 315 is listed (p.Tyr315Tyr; 11:2604688T/C), having been observed in 1 (east Asian) out of 121060 total alleles.
| # | Sample | Method | Observation |
|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences |
|---|
| 1 | germline | unknown | not provided | not provided | not provided | | not provided | not provided | not provided | not provided |
