Fabry disease and evolving story of I198T and A143T: Variants of varying clinical consequence (VVCC)

Fabry disease is an X-linked condition that historically was thought to only affect males, but it is well known that females can also be equally affected. With the advent of newborn screening, understanding genotype-phenotype correlations, especially among variants of uncertain significance, has become essential. Two such GLA variants, p.Ile198Thr (I198T) and p.Ala143Thr (A143T) are associated with later-onset disease, though their pathogenicity remains debated. A cohort of 21 individuals (4 males, 17 females; ages 8-79 years) with these two genotypes from the University of Minnesota is presented here with their phenotypic characterization. In the I198T subgroup, males exhibited higher Lyso-GL3 levels and lower enzymatic activity than females, consistent with X-linked inheritance. A mild cardiac phenotype was observed on imaging in three out of four females over the age of 60, suggesting a potential association between this genotype and a later-onset cardiac risk. The predominant early presenting symptoms and signs included numbness and tingling suggestive of small fiber neuropathy and angiokeratomas, respectively. None of the males in this cohort had any evidence of end-organ damage. Our cohort of p.A143T exhibited no signs of end organ damage, except for one female who presented with concentric left ventricular hypertrophy at a young age. Gastrointestinal symptoms and recurrent headaches were common presenting features. The limited number of males in both cohorts restricts generalizability and underscores the need for larger studies. Given their uncertain pathogenicity and diverse clinical presentations, we propose classifying p.I198T and p.A143T as Variants of Varying Clinical Consequence (VVCC).