Recent months have seen surges of SARS-CoV-2 infection across the globe along with considerable viral evolution. Extensive mutations in the spike protein of variants B.1.1.7, B1.351, and P.1 have raised concerns that the efficacy of current vaccines and therapeutic monoclonal antibodies could be threatened. In vitro studies have shown that one mutation, E484K, plays a crucial role in the loss of neutralizing activity of some monoclonal antibodies as well as most convalescent and vaccinee sera against variant B.1.351. In fact, two vaccine trials have recently reported lower protective efficacy in South Africa, where B.1.351 is dominant. To survey for these novel variants in our patient population in New York City, PCR assays were designed to identify viruses with two signature mutations, E484K and N501Y. We observed a steady increase in the detection rate from late December to mid-February, with an alarming rise to 12.3% in the past two weeks. Whole genome sequencing further demonstrated that most of our E484K isolates (n=49/65) fell within a single lineage: NextStrain clade 20C or Pangolin lineage B.1.526. Patients with this novel variant came from diverse neighborhoods in the metropolitan area, and they were on average older and more frequently hospitalized. Phylogenetic analyses of sequences in the database further reveal that this B.1.526 variant is scattered in the Northeast of US, and its unique set of spike mutations may also pose an antigenic challenge for current interventions.