Interpretation of SLC3A1 and SLC7A9 variants in cystinuria patients: The significance of the PM3 criterion and protein stability

AbstractCystinuria is a genetic disorder caused by defects in the b0,+ transporter system, which is composed of rBAT and b0,+AT coded bySLC3A1 andSLC7A9, respectively. Variants inSLC3A1 andSLC7A9 follow autosomal recessive inheritance and autosomal dominant inheritance with reduced penetrance, respectively, which complicates the interpretation of cystinuria-related variants. Here, we report seven differentSLC3A1 variants and six differentSLC7A9 variants. Among these variants were two novel variants previously not reported:SLC3A1 c.223C  >  T andSLC7A9 c.404A  >  G. In silico analysis using REVEL correlated well with the functional loss uponSLC7A9 variants with scores of 0.8560 –0.9200 and 0.4970–0.5239 for severe and mild decrease in transport activity, respectively. In addition, DynaMut2 was able to predict a decreased protein expression level resulting from theSLC7A9 variant c.313G  >  A with a ΔΔGStability−2.93 kcal/mol. Our study adds to the literature as additional cases of a variant allow applying the PM3 criterion with higher strength level. In addition, we suggest the clinical utility of REVEL and DynaMut2 in interpretingSLC3A1 andSLC7A9 variants. While a decreased protein expression level is not embraced in the current variant interpretation guidelines, we believe in silico protein stability predicting tools could serve as evidence of protein function loss.
Source: Urolithiasis - Category: Urology & Nephrology Source Type: research