rs587780077

rs587780077 represents three possible missense variants at one location in the VHL gene on chromosome 3: c.445G>T, c.445G>A and c.445G>C, representing at the protein level p.Ala149Ser or A149S, p.Ala149Thr or A149T, and p.Ala149Pro or A149P, respectively. [Note that older literature using a previous numbering schema for this gene exists, which on average yields cDNA positions 213nt higher and protein positions 71aa higher.] The best known of these variants is probably c.445G>T (p.Ala149Ser), because of it's potential connection to American folk history. Specifically, the rs587780077(T) variant is considered to be a dominantly inherited pathogenic variant for Von Hippel-Lindau syndrome, which may lead to high blood pressure, racing hearts, severe headaches and too much adrenaline and other "fight or flight" stress hormones. Notably, this variant was discovered in 1998 in the McCoy kindred of West Virginia, best known for their part in the Hatfield-McCoy fued. As discussed in several articles (most notably perhaps this one), due to the associated adrenal gland tumors, this VHL gene mutation provides a possible biological rationale for the "hair-trigger rage and violent outbursts" associated with this clan. Historically, the first rs587780077 pathogenic variant reported was c.445G>A (p.Ala149Thr), and in ClinVar today, it is also annotated as pathogenic for Von Hippel-Lindau syndrome. As for the third alternate allele, c.445G>C (p.Ala149Pro) is considered in ClinVar to be a variant of uncertain significance, but at least one prediction source reports it as likely to also be pathogenic.