Description
p.Thr153Met (c.458C>T) in exon 2 of the KCNQ1 gene (NM_000218.2) Chromosome location 11:2549229 C / T Found in a patient with one-sided sensorineural hearing loss and atrial flutter during infancy. No confirmed diagnosis of LQTS by EKG or exercise testing. We classify this as a VUS, probably, benign, given its relatively high frequency in the broader population. Specifically, this variant has been reported in 46 individuals in the gnomAD database: 12 African-ancestry individuals (for the highest MAF: 0.05%), 28 non-Finnish European-ancestry individuals (MAF 0.02%), 3 Latinos, 2 south Asians, and 1 “Other†ancestry individual. Overall MAF in gnomAD is 0.017%. Of note: Whiffin et al (2017) have proposed that variants with a minor allele frequency greater than 0.0008% are unlikely to be pathogenic in LQTS. This variant has not previously been reported in a clear, clinically-confirmed case of LQTS. It was reported by Kapplinger et al. (2009) in one patient out of 2500 tested for LQTS at Familion laboratory. Of note is the lack of clinical phenotyping data on this cohort, the low genetic testing yield of 36% (vs. 70% in cohorts with firm diagnoses of long QT), indicating that some individuals in the cohort likely do not have the condition, and the lack of clarity regarding which variants were seen alongside another clearly-pathogenic variant (9% of the cohort had multiple variants). The Laboratory for Molecular Medicine at Harvard reports in ClinVar that they saw this variant in a genome or exome case but did not do a complete review. The Threonine at location 153 is not highly conserved across species. In fact, Methionine is the default amino acid in at least 1 mammalian species (elephant). There are no Likely Pathogenic or Pathogenic variants listed in ClinVar within 5 amino acids to either side, indicating that this portion of the protein might be tolerant of change. It is not entirely possible to tell from the location within the KCNQ1 protein if a variant may cause disease. When Kapa et al. (2009) compared 388 “clinically definite†LQTS probands to ~1300 healthy controls, they found that while controls do have variants in all regions of the protein, LQTS cases were much more likely to have missense variants in the C-terminal cytoplasmic region of the KCNQ1 protein (amino acid residues 349-676), the pore region, transmembrane region, or linker region (residues 122-348)—rather than in the N-terminal domain (residues 1-121). This variant does fall within the pore/transmembrance/linker region.
| # | 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 |
