COL18A1 and angioedema: A variant may be classified as a VUS when: (a) there is insufficient evidence to support a more definitive classification of the variant as either likely pathogenic or benign, despite being identified in a gene known to be related to HAE-nC1-INH; (b) it is identified in a gene of uncertain significance but the nature of the variant suggests it may be causative of angioedema phenotype (i.e. truncating variant); (c) a variant lacking evidence of pathogenicity is identified in a known disease causing gene unrelated to angioedema phenotype.