ClinVar Genomic variation as it relates to human health

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Reported in 1 proband; ExAC: 5/10404 African chromosomes; ClinVar: 1 VUS

In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26159999, 26332594, 32797034, 25637381, 22581653, 24055113, 29197658, 25351510, 19841300, 30571187, 19716085, 28988457, 35130036, 32048431, 23396983, 36293497, 28794082)

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 153 of the KCNQ1 protein (p.Thr153Met). This variant is present in population databases (rs143709408, gnomAD 0.05%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 19716085, 25351510). ClinVar contains an entry for this variant (Variation ID: 67075). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on KCNQ1 protein function. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on KCNQ1 function (PMID: 30571187). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Criteria: PS4_Moderate, PM1

This missense variant replaces threonine with methionine at codon 153 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). A functional study has shown the variant to result in a partially reduced sodium current density compared to the wild type (PMID: 30571187). This variant has been reported in a few individuals affected with long QT syndrome (PMID: 19716085, 28794082, 29197658). One of these individuals carried a disease-causing variant in a different gene that could explain the observed phenotype (PMID: 28794082). This variant has also been observed in an individual affected with hypertrophic cardiomyopathy (PMID: 23396983) and in another individual who experienced sudden unexplained death (PMID: 36293497). This variant has been identified in 49/282700 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The relatively high frequency of this variant in the general population suggests that this variant is unlikely to be disease-causing. However, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

This missense variant replaces threonine with methionine at codon 153 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). A functional study has shown the variant to result in a partially reduced sodium current density compared to the wild type (PMID: 30571187). This variant has been reported in a few individuals affected with long QT syndrome (PMID: 19716085, 28794082, 29197658). One of these individuals carried a disease-causing variant in a different gene that could explain the observed phenotype (PMID: 28794082). This variant has also been observed in an individual affected with hypertrophic cardiomyopathy (PMID: 23396983) and in another individual who experienced sudden unexplained death (PMID: 36293497). This variant has been identified in 49/282700 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The relatively high frequency of this variant in the general population suggests that this variant is unlikely to be disease-causing. However, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

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.

This variant has been reported in the following publications (PMID:19716085).